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Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy

Regular readers will no doubt recall that TTR amyloidosis, also known as senile systemic amyloidosis, is a prime suspect for the mechanism that limits human life span to the 110-120 range. Based on evidence from autopsies performed on supercentenarians, those who through luck, genes, and lifestyle manage to survive past the age of 110, these outliers are largely slain by a buildup of amyloid deposits that leads to clogging of blood vessels and ultimately to heart failure.

Transthyretin, or TTR is a protein involved in the transport of a thyroid hormone through the bloodstream. It produces amyloid when it misfolds, something that only becomes threatening in the young for the few unfortunate individuals who inherit a faulty TTR gene. There is some research aimed at producing a therapy for this inherited form of TTR amyloidosis, and the SENS Research Foundation has funded it with an eye to also producing ways to address the age-related form. If there was a good way to periodically clear this amyloid from our tissues, that is all that would need to be done for most people in order to eliminate this very slow-moving contribution to degenerative aging.

Here is an eye-opening piece of research that shows a significant correlation between a minor variant of the TTR gene and life expectancy differences driven by cardiovascular disease and other risks. The effect is surprisingly large for a minor genetic variation, from what I recall of similar research in recent years, and I'd certainly want to see this result replicated before taking it as read. It is still a good argument for bumping up the priority for research into amyloid clearance therapies, though one could argue that perhaps other mechanisms are also at work here, since levels of thyroid hormones seem to be important in longevity:

Transthyretin can cause amyloidosis attributable to destabilization of transthyretin tetramers in plasma. We tested the hypothesis that genetic stabilization of transthyretin associates with reduced risk of vascular disease and increased life expectancy. We included 68,602 participants from 2 prospective studies of the general population. We genotyped for 2 stabilizing genetic variants in the transthyretin gene (TTR), R104H and T119M, and determined the association of genotypes with plasma levels of transthyretin, measures of thyroid function, risk of vascular disease, and life expectancy.

During a mean follow-up of 32 years, 10,636 participants developed vascular disease. We identified 321 heterozygotes for T119M (frequency, 0.47%); R104H was not detected. First, mean plasma transthyretin and thyroxine levels were increased by 17% and 20%, respectively, in heterozygotes versus noncarriers, demonstrating functionality of this variant in the general population. Second, corresponding hazard ratios were 0.70 for all vascular diseases, 0.85 for cardiovascular disease, 0.45 for cerebrovascular disease, 0.47 for ischemic cerebrovascular disease, and 0.31 for hemorrhagic stroke. The cumulative incidence of cerebrovascular disease as a function of age was decreased in heterozygotes versus noncarriers.

Third, median age at death from all causes, from vascular and cerebrovascular diseases, and after diagnosis of vascular disease, and median age at diagnosis of vascular disease, was increased by 5 to 10 years in heterozygotes versus noncarriers.

Link: http://dx.doi.org/10.1161/ATVBAHA.113.301273

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