Declining Microcirculation as an Important Aspect of Aging

Tissues are supported by dense and intricate networks of capillaries, hundreds passing through any square millimeter cross-section. Many studies have shown that capillary density decreases with age, which is perhaps another of the many results of faltering tissue maintenance due to the decline in stem cell activity, or alternatively, a specific dysregulation of the processes of angiogenesis at the small scale, resulting from inappropriate cellular reactions to rising levels of damage and chronic inflammation. Fewer capillaries means a lesser delivery of nutrients and oxygen, and we might well wonder to what degree this contributes to atrophy and dysfunction in energy hungry tissues such as muscles and the brain.

In this context, consider of the loss of muscle mass and strength that occurs with aging, known as sarcopenia. While sarcopenia is associated with a long, long list of potential contributing mechanisms, arguably the best evidence suggests that this loss of muscle capacity is caused by the declining activity of muscle stem cell populations. This connects well with a decline in capillary density, in that we can theorize either side as cause or consequence of the other. Another possible contributing factor is age-related mitochondrial dysfunction. Given that mitochondria are the power plants of the cell, responsible for transforming energy from nutrients into a form that cells can use, here too the possible connections to declining capillary density are obvious.

The two different approaches to this challenge are quite different. On the one hand, the first and more mainstream approach would be to attempt to override changes in the regulation of angiogenesis, forcing different expression levels in various regulatory proteins in order to generate greater generation of blood vessels. This strategy can produce benefits, but because it fails to address the underlying causes, the benefits are necessarily limited. The damage of aging marches on, causing all of its other consequences. One might look at past efforts to control raised blood pressure or chronic inflammation to see the plausible beneficial outcomes that can emerge from tackling important facets of aging in ways that do not repair the causes. The second, and as yet less popular - but better! - approach is to repair the damage that causes aging, and thus remove the dysregulation in angiogenesis and tissue maintenance that way. Sadly, this path forward is nowhere near as popular and well funded as it should be.

A Microcirculatory Theory of Aging

The term "microcirculation" in contrast with macrocirculation (which is the flow of blood to and from organs), refers to a network of terminal vessels comprising arterioles, capillaries and venules that are less than 100 μm in diameter. In other words, the microcirculation is defined as the blood flow through the smallest vessels in the vasculature and are embedded within organs and tissues, which facilitate the exchange of biological material between the blood and tissue via its large surface area and low blood velocity in these regions. For organs to function well, there must be sufficient perfusion throughout the tissue in the form of intact and appropriate microcirculatory vascularization.

There is a substantial number of studies presenting strong evidence of decreased vessel density with age, indicating an age-associated failure of vascular recovery in organs such as the brain in animals and humans alike. In studies involving aged rodents: healthy senescent rats (29 months) experienced a loss of about 40% of arteriolar density on the cortical surface compared with young adult rats (13 months). In the hippocampus of aged rats, there was a 20% decrease in capillary number, 3% decrease in capillary length, and 24% increase in intercapillary distance. Comparable reductions could also be found in other brain regions including the brain stem, cortex, and white matter. In studies involving aged humans: Capillary density decreased by 16% in the calcarine cortex while vascular density decreased by 50% in the paraventricular nucleus, frontal cortex, and putamen. Importantly, angiogenesis has been found to be impaired in aged tissues, which could contribute to the significant decreases in vascular density and number that has been reported.

Factors of vascular aging are reported to be closely associated with chronological age. Indeed, alterations in vascular mechanics and structure are related with vascular aging, resulting in less elastic arteries and diminished arterial compliance. Furthermore, the increased diffusion distance for oxygen caused by reduced capillary numbers and density, gives rise to heterogeneous perfusion, where the close proximity of perfused capillaries and non-perfused capillaries triggers alterations to oxygen extraction even when blood flow to the tissue is conserved.

Under normal physiological conditions, the microcirculatory blood flow is adapted to the metabolic levels of human tissues and organs, so the physiological functions of various organs in the human body can function as they should. Once the microcirculation of the human body is impaired, cells would not be able to get enough nutrition and oxygen, and meanwhile, CO2 and metabolic products, including those that are toxic, cannot be removed and will accumulate. Consequently, deterioration of physiological functions of cells and then organs that are necessary for survival and reproduction will occur. Microcirculatory impairment arises in adulthood and becomes progressively impaired with aging; the corresponding tissue system or internal organs are affected and unable to function normally, which eventually lead to aging. Therefore, aging is the process of continuous impairment of microcirculation in the body.

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