Mechanisms of homocysteine toxicity on connective tissues: implications for the morbidity of aging

Area of Science:

• Biochemistry
• Pathology
• Gerontology

Background:

• Chronic moderate hyperhomocysteinemia is linked to several late-life diseases.
• These conditions resemble homocystinuria but develop over years of elevated homocysteine (Hcy) levels.
• Hcy toxicity is proposed to result from chemical reactions with vital molecules, primarily proteins.

Purpose of the Study:

• To propose a causal role for chronic moderate hyperhomocysteinemia in common late-life diseases.
• To explain the mechanism of Hcy-induced multisystem toxicity.
• To identify potential molecular targets of Hcy damage.

Main Methods:

• The study is theoretical, proposing a mechanism based on existing knowledge.
• It analyzes the chemical reactivity of homocysteine with biological molecules.
• It examines the structural and functional implications of Hcy-protein adducts.

Main Results:

• Elevated Hcy levels lead to Hcy-adduct formation in proteins.
• This modification is time and concentration-dependent, causing loss of protein function.
• Long-lived proteins, like fibrillin 1, are susceptible to irreversible homocysteinylation, leading to cumulative damage.

Conclusions:

• Chronic moderate hyperhomocysteinemia is proposed as a causal factor in diseases such as occlusive vascular disease, cognitive decline, osteoporosis, and presbyopia.
• Homocysteine (Hcy) toxicity stems from its reaction with proteins, forming Hcy-adducts that impair function.
• Epidermal growth factor (EGF)-like domains in proteins like fibrillin 1 may be preferential sites for homocysteinylation, contributing to disease pathogenesis.