An Angiogenesis Hypothesis of Aging

There are many theories of aging, some with a broader scope, focused on the high level or the evolutionary explanation for aging and all of its variations in pace, and others that are more limited, examining just a few aspects of age-related decline and in search of the principle mechanisms that cause that decline. Today’s example is one of the more compact theories of aging, restricting itself to considering the creation and maintenance of the network of capillaries that supplies tissues. The oxygen and nutrients carried by blood cannot perfuse far beyond blood vessels, and so every last cubic millimeter of the body must be reached by the circulatory system, where it branches out into the smallest and most numerous blood vessels, those too small to be discerned by the naked eye.

What does it tell us about aging that capillary density appears to decrease in older mammals? Cardiovascular disease is of course well known to be a major cause of mortality, but much of the focus there is on the stiffening of major blood vessels, hypertension, and dysfunction and remodeling of heart tissue. These are larger-scale phenomenon, undeniably important, but does their importance overwhelm what is going on at the small scale, in the network of capillaries throughout the body? The researchers here argue that the small scale is just as important, and unfortunately overlooked.

One item to bear in mind when reading the paper here is that mitochondrial dysfunction of a fairly general sort, a global loss of function, is implicated in many aspects of aging. Mitochondria are the power plants of the cell, using nutrients to generate chemical energy store molecules. One might ponder on a connection between reduced capillary coverage and reduced mitochondrial activity due to a lack of nutrients; certainly a great deal of neurodegenerative disease research focuses on vascular dysfunction and consequently reduced delivery of oxygen and nutrients to the brain.

The other principle point made by the authors of this paper is that may be a short path to therapies that can partially compensate for the loss of capillary density by spurring angiogenesis, the creation of new blood vessels. Angiogenesis has been fairly well studied in the cancer research community and elsewhere, and there are a wide range of targets and drug candidates to either increase or decrease angiogenesis rates. Since testing effectiveness would be a comparatively rapid process, it might be worth trying this approach even though it doesn’t address the underlying reasons for the loss of capillary density. As to what those reasons might be, we can speculate; perhaps loss of stem cell activity, perhaps changes in the extracellular matrix, or perhaps chronic inflammation that disrupts the normal processes of regeneration and angiogenesis, to pick a few options for further discussion.

Pro-Angiogenesis Therapy and Aging: A Mini-Review

Elderly persons may experience a range of medical conditions: a fatal disease (cancer, stroke, etc.), chronic afflictions (diabetes, arthritis, atrial fibrillation, etc.), and troubling lesser ailments. The last is a collective term for 5 minor symptoms and signs of old age, which include general muscle weakness, cold intolerance, minor memory lapses, skin wrinkles, and the slow healing of bruises or abrasions in the skin. The lesser ailments of aging (LAA) are the focus of this review and are grouped together here because they may have a common vascular cause and may be treatable, as next explained.

It is well recognized that atherosclerosis in arteries and arterioles leads to major illnesses – stroke, heart disease, and peripheral vascular disease. Later in life, changes occur at the terminal end of the vascular tree, where capillaries develop looping, kinking, and extensive tortuosity. Not commonly appreciated is that capillaries also undergo significant regression in absolute number. Over 40 published studies have reported a reduced capillary density throughout the body of aged animals and people.

The development and maintenance of capillaries depend on angiogenesis – i.e., on genetically programmed levels of angiogenic growth factors (AGFs). During early growth and maturation of the body, the development and function of various organ systems involve rising levels of AGFs and an expanding microcirculation. However, during old age, people and animals show declining levels of such factors in various organ systems, paralleling the reduced capillary density. Thus, old age represents a deficiency condition for angiogenesis factors, much like hormone levels that are decreased in the elderly.

The idea that the lesser ailments may be due in part to age-associated diminished capillary density and AGFs is termed “the angiogenesis hypothesis of aging.” Its corollary suggests that treatment with exogenous angiogenic factors should restore reduced capillary density in areas experimentally depleted of capillaries and may improve function in areas of naturally impaired microcirculation. Recombinant angiogenic factors have been shown to induce new capillary formation in ischemic and normoxic tissues within days, as observed in numerous animal studies. Thus, in theory, pro-angiogenesis therapy may ease the LAA after they have appeared or delay their development. This is in contrast to the pathology in the larger blood vessels, where fatty plaques and cholesterol deposits cannot be readily eliminated once acquired but only prevented in the decades before old age by avoiding risk factors – i.e., obesity, diabetes, hypertension, etc.

Countless theories have been advanced to explain aging in people but none has led to a widely accepted treatment based on reversing an underlying cause. Physiological aging is commonly assumed to be due to various causes. Indeed, if aging is the result of several enfeebling influences, then lessening any one might ease its symptoms and signs. Again, there is abundant evidence in the literature that a reduced capillary density and a waning angiogenesis occur during old age. It seems likely that these linked changes influence the physiological state of the aged body – accounting for its fading functions and possibly for the lesser ailments. A reduced cerebral capillary density may contribute to the more profound cognitive problems of old age; e.g., Alzheimer’s disease.

Animal studies establish that exogenous AGFs generate new capillaries. While numerous investigators have administered recombinant AGFs to relieve specific conditions of ischemia in the human body, to my knowledge, no gerontologist has proposed pro-angiogenesis therapy for moderating or delaying the widespread reduced microcirculation occurring during old age. Therapeutic pro-angiogenesis seems a tenable consideration for the lesser ailments of the elderly. The extensive data referenced here bring to mind George Orwell’s admonition “To see what is in front of one’s nose needs a constant struggle.”

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