Fight Aging!

Medin is one of a small number of proteins that can misfold in ways that encourage other molecules of the same protein to also misfold, linking to form solid aggregates. While medin aggregation seems near ubiquitous in old people, the harms caused by this form of amyloidosis are far less well studied than is the case for, say, the amyloid-β characteristic of Alzheimer's disease. Still, evidence supports a role for medin in causing age-related dysfunction of the cerebral vasculature, and it is also suggested that this can provoke greater pathology in neurodegenerative conditions such as Alzheimer's disease.

In the open access paper I'll point out today, researchers point out evidence for rising numbers of senescent cells in the aged vasculature to precede and encourage medin aggregation. These cells secrete disruptive signaling, some of which is encapsulated in extracellular vesicles. Here, the vesicles generated by senescent cells are found to contain medin in greater amounts than those generated by normal cells. This is one of many lines of research that support the use of senolytic therapies to clear senescent cells as a possible approach to the treatment of neurodegenerative conditions. Early senolytics are in clinical trials, but it remains to be seen as to whether that part of the longevity industry focused on building new senolytic therapies will pursue the rejuvenation of brain tissue with any great vigor, or any time soon.

Senescence and extracellular vesicles: novel partners in vascular amyloidosis

The most common human amyloid is aortic medial amyloid (AMA), caused by aggregation of a 50-amino acid peptide called medin, which is cleaved by an unknown mechanism from its parent protein, milk fat globulin EGF-factor 8 (MFGE8). Medin is present in the vessel wall of 97% of Caucasians aged over 50- years, yet despite its prevalence in the ageing population there is a very limited understanding of the mechanisms driving AMA. Despite several forms of amyloidosis, including AMA and Alzheimer's disease (AD), being frequently associated with ageing, there has been limited research to date on the effect of cellular 'ageing', termed senescence, on amyloidosis.

Senescent cells accumulate in the vasculature with age and undergo a range of phenotypic changes, including extracellular matrix (ECM) remodelling and increased secretion of inflammatory mediators. Researchers have confirmed a strong correlation between age and medin in the ECM of the medial layer of human aortic tissue. In vitro studies, using human vascular smooth muscle cells (VSMCs), demonstrated that the ECM synthesised by senescent cells contained medin in a fibril-like form. This was in contrast to the small, round aggregates found in the ECM from healthy, proliferative VSMCs, suggesting senescent cells create an environment permissive for medin aggregation. Further mechanistic studies found that small extracellular vesicles (sEVs) secreted from VSMCs carried medin as a cargo and were responsible for medin release and also its aggregation in the ECM. Importantly, senescent VSMCs showed enhanced sEV secretion and senescent sEVs could accelerate medin aggregation compared with sEVs from proliferative VSMCs.

The pathological effects of medin accumulation in the vasculature, as well as the forms of medin responsible for inducing damage, remain poorly understood. Studies have shown that small medin aggregates can induce endothelial cell dysfunction and inflammation while accumulation of fibrillar amyloid species can contribute to weakening and stiffening of the vessel wall. These effects may be particularly relevant to the cerebrovasculature as a recent study has shown that medin accumulates in the cerebral vessels with age and may enhance Aβ formation, leading to vascular stiffening in the brain and increased CAA burden. These data suggest that medin may represent a new therapeutic target for AD and CAA, to maintain a functioning and healthy cerebral environment during ageing.