Homocysteine private
MTHFR Polymorphism

Author: Gianpiero Pescarmona
Date: 12/03/2016


Elevated plasma homocysteine levels in centenarians are not associated with cognitive impairment. 2000

    Previous reports have shown elevated plasma total homocysteine (tHcy) levels in elderly person with impaired cognition.

To study the association between cognitive status and plasma tHcy levels in centenarians.

Cross-sectional survey.

Centenarians living in two northern Italian provinces.

Thirteen cognitively normal centenarians, ten cognitively impaired not-demented centenarians, and 34 demented centenarians with a clinical diagnosis of Alzheimer's disease (AD).

Blood levels of homocysteine's biological determinants vitamin B12, folate, and vitamin B6.

Elevated plasma tHcy levels (>17 micromol/l) were common in the general population (77% of normal centenarians, 100% of cognitively impaired not-demented centenarians, 82% of AD centenarians). Demented centenarians had the lowest folate serum levels. Low or borderline vitamin B12 serum levels (<221 pmol/l) and low vitamin B6 plasma levels (<11.7 nmol/l) were found in 33 and 66% of all centenarians independently of cognitive status. Among demented centenarians only plasma tHcy correlated inversely with both serum vitamin B12 and folate. No significant difference was found for plasma tHcy levels among the three diagnostic groups, even after adjusting for B vitamin levels.

Hyperhomocysteinemia is very common among centenarians, probably due to vitamin deficiencies, but does not seem to be associated with cognitive impairment.

Elevated plasma total homocysteine in centenarians., 2004

  • Homocysteine (Hcy) is a sulfur-containing metabolite of methionine and is an emerging independent risk factor for atherosclerosis. Previous studies have shown that age, gender, renal function and folic acid intake are the main factors influencing total plasma Hcy levels in humans. A unique approach to the science of human longevity is the natural model of centenarians. The objective of this study was to verify whether the previously determined risk factors for atherosclerosis and atherosclerosis-related diseases change with age and, finally, to establish the vitamin nutritional status role. We studied 54 centenarians (14 males and 40 females) aged between 100-107 years (mean age 102.6+/-1.8 years) living in Sicily (Italy), recruited via the Registry Office, and compared them with three control groups composed of subjects with different age ranges. Total plasma Hcy, folate, vitamin B12 and pyridoxal phosphate (PLP) levels were compared between the groups by the Student's t test. The comparison between centenarians and <65-year old, randomly selected individuals showed that in centenarians the mean value of serum creatinine levels was 18 micromol/l (p=0.000) higher, the mean total Hcy value was 22 micromol/l higher (p=0.000), the mean PLP value was 17.9 nmol/l lower (p=0.000), the mean folate level was 2.1 nmol/l lower (p<0.001) and vitamin B12 was 70.5 pmol/l lower (p=0.000). The comparison between centenarians and >65-year old, randomly selected individuals showed that in centenarians the mean value of serum creatinine levels was 8 micromol/l higher (p=0.037), the mean total Hcy value was 11.6 micromol/l higher (p=0.000) and the mean PLP value was 4.2 nmol/l higher (p=0.000). It seems that centenarians are protected by some mechanism (maybe genetic) that allows them a long survival despite the high value of homocysteinemia. On the other hand, it can by hypothesized that good vitamin intake is essential to live over 100 years.

Hpmocysteine centenarians

If homocysteine is high in centenarian and low in Down Syndrome (progeria) which is the mechanism?

Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review. 2014

  • Although normally folic acid is given during pregnancy, presumably to prevent neural tube defects, the mechanisms of this protection are unknown. More importantly it is unclear whether folic acid has other function during development. It is known that folic acid re-methylates homocysteine (Hcy) to methionine by methylene tetrahydrofolate reductase-dependent pathways. Folic acid also generates high-energy phosphates, behaves as an antioxidant and improves nitric oxide (NO) production by endothelial NO synthase. Interestingly, during epigenetic modification, methylation of DNA/RNA generate homocysteine unequivocally. The enhanced overexpression of methyl transferase lead to increased yield of Hcy. The accumulation of Hcy causes vascular dysfunction, reduces perfusion in the muscles thereby causing musculopathy. Another interesting fact is that children with severe hyperhomocysteinaemia (HHcy) have skeletal deformities, and do not live past teenage. HHcy is also associated with the progeria syndrome. Epilepsy is primarily caused by inhibition of gamma-amino-butyric-acid (GABA) receptor, an inhibitory neurotransmitter in the neuronal synapse. Folate deficiency leads to HHcy which then competes with GABA for binding on the GABA receptors. With so many genetic and clinical manifestations associated with folate deficiency, we propose that folate deficiency induces epigenetic alterations in the genes and thereby results in disease.

Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity. 1997

  • Genetic factors are likely to affect human survival, since twin studies have shown greater concordance for age of death in monozygotic compared to dizygotic twins. Coronary artery disease is an important contributor to premature mortality in the UK. Accordingly, we have chosen genes associated with cardiovascular risk, apo E/apo C-I, angiotensin converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An association study was performed by comparing allele and genotype frequencies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger than 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencies were significantly different in the elderly women compared to the younger sample (P < 0.05). No difference was observed in the elderly men. At the neighbouring apo E gene, we only observed a difference between genotypes in the elderly women and the young sample; however, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women. In contrast to previous studies, apo E2 was not overrepresented in the elderly men or women. Thus, the proposition that apo E2, E3 and E4 protein isoforms are themselves functionally associated with increasing risks for early death, may be too simplistic. The I/I ACE was depleted in the elderly males but not the elderly females. Furthermore, significant differences were observed between ACE genotypes in elderly men and elderly women. These data suggest that the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is generally consistent with a previous study which found decreased frequencies of the I allele in French centenarians compared to younger controls. However, these results are apparently paradoxical, since others have suggested that the I allele is associated with increased cardiovascular risk. Clarification of the overall effect of a genotype on survival will be vital if therapies are to be considered which target specific genetic variants.

cognitive deficit homocysteine

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