This essay begins by proposing that muscle weakness of old age from sarcopenia is due in large part to reduced capillary density in the muscles, as documented in 9 reports of aged persons and animals. Capillary density (CD) is determined by local levels of various angiogenic factors, which also decline in muscles with aging, as reported in 7 studies of old persons and animals. There are also numerous reports of reduced CD in the aged brain and other studies showing reduced CD in the kidney and heart of aged animals. Thus a waning angiogenesis throughout the body may be a natural occurrence in later years and may account significantly for the lesser ailments (physical and cognitive) of elderly people. Old age is regarded here as a deficiency state which may be corrected by therapeutic angiogenesis, much as a hormonal deficiency can be relieved by the appropriate hormone therapy. Such therapy could employ recombinant angiogenic factors which are now commercially available.
Angiogenesis directs development of the brain's microcirculation during antenatal and postnatal development, but its role later in life is less well recognized. I contend that during senescence a reduced cerebral capillary density accounts in part for the vascular cognitive impairment observed in many older persons and possibly for some forms of Alzheimer's disease. I propose that neuroangiogenesis is essential throughout adult life for maintaining the microcirculation of the cerebral cortex and elsewhere in the brain and that it commonly declines with old age. To support this hypothesis I have examined the neurological literature for relevant studies on cerebral capillary density and neuroangiogenesis throughout the three stages of life and in persons with senile dementias. Finally, I discuss therapeutic approaches employing angiogenic factors for treating vascular cognitive impairment and Alzheimer's disease.
Apart from chronic diseases (arthritis, diabetes, etc.), old age is generally characterized by three lesser ailments: muscle weakness, minor memory lapses, and cold intolerance. This trio of complaints may have a common, underlying cause, namely, the age-associated reduced microcirculation in muscles, brain, skin, and elsewhere in the body. The Angiogenesis Hypothesis proposes that old age is in part a deficiency disease due to the decline in angiogenic (AG) factors, resulting in a reduced capillary density (CD) throughout the body. Over fifty published papers document waning levels of AG factors and/or decreased CD in various organ systems of aged animals and people, including those with Alzheimer's disease. The deficiency of AG factors is analogous to that of certain hormones (e.g., testosterone) whose blood levels also decline with age. In theory, therapeutic angiogenesis employing recombinant AG factors is a tenable treatment for the lesser ailments of old age and may improve the later years of human life. An optimal administration route may be intranasal.
It was previously reported from this laboratory that the secondary antibody response can regularly be elicited in vitro from fragments of rabbit lymph node node cultured in Eagle's medium supplemented with normal rabbit serum. Evidence is now presented that physiological levels of hydrocortisone (0.01 to 1.0 µM) can substitute for serum in the culture medium. However, with the omission of serum, serine (0.1 mM) must be included among Eagle's "essential" amino acids for consistent optimal antibody production. In some experiments the addition of insulin (0.5 unit/ml) and vitamin B12 (0.5 µg/ml) has further enhanced the secondary response in this serum-free medium.
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