Supercentenarians and transthyretin amyloidosis: The next frontier of human life extension

Coles, L. Stephen; Young, Robert

doi:10.1016/j.ypmed.2012.03.003

Cited by 22 publications

(15 citation statements)

References 5 publications

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“…114, 115 Amyloid formation by wild-type TTR causes a similar cardiomyopathy improperly named senile systemic amyloidosis (SSA), which affects mostly Caucasian men over the age of 60 116 and is a major cause of death among centenarians. 117 A third disease is familial amyloidotic polyneuropathy (FAP), which affects ~10,000 people, predominantly in Portugal, Sweden, and Japan. In FAP, mutant TTR forms amyloid deposits in the kidneys, gastrointestinal (GI) tract, and peripheral nervous system (PNS), leading to progressive dysfunction and death within ~5 years.…”

Section: Molecular Tweezers Modulate Abnormal Protein Aggregationmentioning

confidence: 99%

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

2016

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Molecular tweezers represent the first class of artificial receptor molecules that made the way from a supramolecular host to a drug candidate with promising results in animal tests. Due to their unique structure, only lysine and arginine are well complexed with exquisite selectivity by a threading mechanism, which unites electrostatic, hydrophobic and dispersive attraction. However, tweezer design must avoid self-dimerization, self-inclusion and external guest binding. Moderate affinities of the molecular tweezers towards sterically well accessible basic amino acids with fast on and off rates protect normal proteins from a potential interference with their biological function. However, the early stages of abnormal Aβ, α-synuclein, and TTR assembly are redirected upon tweezer binding towards the generation of amorphous non-toxic material that can be degraded by the intracellular and extracellular clearance mechanisms. Thus, specific host–guest chemistry between aggregation-prone proteins and lysine/arginine binders rescues cell viability and restores animal health in models of AD, PD, and TTR amyloidosis.

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Section: Molecular Tweezers Modulate Abnormal Protein Aggregationmentioning

confidence: 99%

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

2016

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“…Whilst aging is a nearly universal occurrence, it should be noted that other medical problems such as muscle wastage leading to sarcopenia, reduction in bone mass and density leading to osteoporosis, increased arterial hardening resulting in hypertension, atherosclerosis, and brain tissue atrophy resulting in dementia, all of which are nearly universal in humans, are classified as diseases in need of medical interventions (Bierman, 1985; WHO, 1994; Izaks and Westendorp, 2003; Gems, 2011). Also, autopsy studies indicate that amyloidosis may be almost universal in elderly people (Blumenthal, 2002) and, in autopsies performed by the Supercentenarian Research Foundation (SRF), amyloidosis has been identified as the cause of death in about 70% of people over 110 years of age (Coles and Young, 2012). Should we remove amyloidosis from medical textbooks as an age-related disease just because it happens to occur in almost every elderly subject?…”

Section: Is Aging a Disease?mentioning

confidence: 99%

It is time to classify biological aging as a disease

et al. 2015

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“…89 Neurodegenerative diseases such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease, in all of which protein misfolding is a prominent feature, emerge with aging. The induction of aggregation involves a crystallizationlike seeding mechanism by which a specific protein is structurally corrupted by its misfolded conformer.…”

Section: Healthy Aging and Protein Misfoldingmentioning

confidence: 99%