Fight Aging!

Minoxidil is, of course, the well known basis for certain popular hair growth products. That outcome was an accident, however, as the compound originally entered clinical trials - some 30 years ago - as a possible treatment for hypertension, or chronic raised blood pressure. The primary mechanism of interest is that minoxidil spurs greater deposition of elastin in blood vessel walls and other tissues, thereby reversing a fraction of the progressive loss of elastin that takes place over the course of aging.

Elastin, as one might guess from the name, is a component of the extracellular matrix responsible for the elasticity exhibited by tissues such as skin and blood vessels. Hypertension is caused by the age-related stiffening of blood vessels, which leads to a dysregulation of pressure control systems in our biochemistry. This then speeds up the progression of atherosclerosis and heart failure, and in addition produces an accelerated rate of capillary rupture and consequent damage in delicate tissues such as the brain and kidney. It is a very import aspect of age-related degeneration.

It is interesting to see researchers still working on minoxidil. The original clinical trials for hypertension, while leading to an approved drug, showed that minoxidil causes edema around the heart at useful doses for the elastin deposition effect, a potentially severe consequence. For me, that is more than enough to reconsider its use in this way. During the early studies and trials, hair growth in the patients was noted, and the rest of the development program thereafter is history. It is possible that now, with a far greater ability to take a small molecule as a starting point and build different versions with different characteristics, it is plausible to build a minoxidil analog that doesn't have the serious side-effects at usefully high doses, where that was simply not possible in earlier decades. We shall see.

Arterial wall elastic fibers, made of 90% elastin, are arranged into elastic lamellae which are responsible for the resilience and elastic properties of the large arteries (aorta and its proximal branches). Elastin is synthesized only in early life and adolescence mainly by the vascular smooth muscle cells (VSMC) through the cross-linking of its soluble precursor, tropoelastin. In normal aging, the elastic fibers become fragmented and the mechanical load is transferred to collagen fibers, which are 100-1000 times stiffer than elastic fibers.

Minoxidil, an ATP-dependent K+ channel opener, has been shown to stimulate elastin expression in vitro and in vivo in the aorta of young adult hypertensive rats. Here, we have studied the effect of a 3-month chronic oral treatment with minoxidil (120 mg/L in drinking water) on the abdominal aorta structure and function in adult (6-month-old) and aged (24-month-old) male and female mice. Our results show that minoxidil treatment preserves elastic lamellae integrity, which is accompanied by the formation of newly synthesized elastic fibers in aged mice. This led to a generally decreased pulse pressure and a significant improvement of the arterial biomechanical properties in female mice, which present an increased distensibility and a decreased rigidity of the aorta. Our studies show that minoxidil treatment reversed some of the major adverse effects of arterial aging in mice and could be an interesting anti-arterial aging agent, also potentially usable for young female-targeted therapies.

Link: https://doi.org/10.1016/j.cellsig.2019.05.018