It is proposed that chronic moderate
hyperhomocysteinemia has a causal role in a number of common diseases of late life, including occlusive
vascular disease,
cognitive decline,
senile osteoporosis and
presbyopia. These diseases are seen as clinical counterparts of the main manifestations of
homocystinuria (vascular occlusions of arteries and veins,
mental retardation,
osteoporosis and
ectopia lentis, respectively) that develop only after many years of exposure to moderately elevated
homocysteine (Hcy) levels. The multisystem toxicity of Hcy is attributed to its spontaneous chemical reaction with many biologically important molecules, primarily
proteins. The formation of these Hcy-adducts is dependent on time and Hcy concentration and leads to loss or diminution of function of the derivatized molecules. Irreversible homocysteinylation of long-lived
proteins should lead to cumulative damage and progressive clinical manifestations.
Fibrillin 1 is seen as the paradigm of extracellular connective tissue
proteins that are specially susceptible to Hcy (and presumably
Hcy thiolactone) attack. The prominent presence of
epidermal growth factor (
EGF)-like domains in
fibrillin and in many other extracellular
proteins of the coagulation, anticoagulation, and
lipoprotein transport pathways, all of which malfunction in
hyperhomocysteinemia, suggests that
EGF-like domains may be preferential sites of homocysteinylation.