Unique Lipoprotein Phenotype and Genotype Associated With Exceptional Longevity

Barzilai, Nir; Atzmon, Gil; Schechter, Clyde B.; Schaefer, Ernst J.; Cupples, Adrienne; Lipton, Richard B.; Cheng, Suzanne; Shuldiner, Alan R.

doi:10.1001/jama.290.15.2030

Cited by 528 publications

(334 citation statements)

References 40 publications

Supporting

Mentioning

318

Contrasting

Unclassified

Order By: Relevance

“…In a case control study, Ashkenazi Jews were recruited as described (13,14,33). This population derived from an undetermined small number (estimated to be several thousands) of founders.…”

Section: Methodsmentioning

confidence: 99%

“…Health histories were obtained by using a standardized questionnaire. In such visits, the offspring (and participating spouses) underwent similar evaluations as described (13,14,33 Mutation Screening of IGF1 and IGF1R. We screened genomic DNA isolated from blood of centenarians and controls to discover all possible genetic variations in the full coding sequence and intron/exon boundaries of the IGF1 and IGF1R genes by 2D gene scanning (35).…”

Section: Methodsmentioning

confidence: 99%

“…To overcome this shortcoming, we established a unique cohort of individuals with exceptional longevity and their offspring (approximate age 70 years) and age-and sex-matched controls without a family history of unusual longevity; all of Ashkenazi Jewish descent. This group of offspring of individuals with exceptional longevity and their matched controls is a powerful tool for identifying genetically controlled longevity traits and led to the identification of longevity phenotypes such as lipoprotein sizes and the subsequent discovery of corresponding longevity genotypes (13,14). Here, we report the use of this unique cohort to identify partial loss-of-function mutations in the IGF1 receptor (IGF1R) gene that are overrepresented among centenarians compared with controls, suggesting a role for the IGF signaling pathway in human longevity.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Functionally significant insulin-like growth factor I receptor mutations in centenarians

Suh

Atzmon

Cho

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

640

474

View full text Add to dashboard Cite

Rather than being a passive, haphazard process of wear and tear, lifespan can be modulated actively by components of the insulin/ insulin-like growth factor I (IGFI) pathway in laboratory animals. Complete or partial loss-of-function mutations in genes encoding components of the insulin/IGFI pathway result in extension of life span in yeasts, worms, flies, and mice. This remarkable conservation throughout evolution suggests that altered signaling in this pathway may also influence human lifespan. On the other hand, evolutionary tradeoffs predict that the laboratory findings may not be relevant to human populations, because of the high fitness cost during early life. Here, we studied the biochemical, phenotypic, and genetic variations in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls and demonstrated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous mutations in the IGF1R gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan.IGF1 receptor ͉ human longevity ͉ genetic variation

show abstract

“…In a case control study, Ashkenazi Jews were recruited as described (13,14,33). This population derived from an undetermined small number (estimated to be several thousands) of founders.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Functionally significant insulin-like growth factor I receptor mutations in centenarians

Suh

Atzmon

Cho

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

640

474

View full text Add to dashboard Cite

show abstract

“…Good physical function is rated highly among attributes of successful aging in surveys of the general elderly population (Bowling and Dieppe 2005;Rowe and Kahn 1998). Emerging evidence from human and animal studies shows that genetics partially determine exceptional longevity, and associated successful aging phenotypes (Adams et al 2008;Barzilai et al 2006;Barzilai et al 2003;Murabito et al 2012;Newman et al 2011). Offspring of parents with exceptional longevity (OPEL) who are more likely to carry longevity-associated genotypes may age more successfully than offspring of parents with usual survival (OPUS) (Barzilai et al 2006;Barzilai et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Association of exceptional parental longevity and physical function in aging

Ayers

Barzilai

Crandall

et al. 2014

AGE

Self Cite

View full text Add to dashboard Cite

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevityassociated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited. The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance (p=0.009) and gait speed (p=0.002). Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.

show abstract

“…Earlier studies showed that carriers of the CETP variant had higher levels of protective HDL particles than people with normal CETP. 5 In another previous study, 6 "we saw there was a connection between the CETP mutation and longevity in Ashkenazi Jewish centenarians, " said Lipton. "We also found that carriers had better mental status.…”

Section: Healthy Humansmentioning

confidence: 98%

Cholesterol metabolism ADds up

Osherovich¹

2010

Science-Business eXchange

View full text Add to dashboard Cite

Reports by independent teams at Dartmouth College and Albert Einstein College of Medicine of Yeshiva University suggest that blocking production and transport of cholesteryl esters, the extracellular form of cholesterol, could be useful for treating Alzheimer's disease.1,2 The findings reveal two cholesteryl ester metabolism enzymes, ACAT1 and CETP, as potential AD targets and could represent a repurposing opportunity for a quartet of pharma companies that have studied the enzymes in the cardiovascular space.Cholesteryl esters consist of interlinked molecules of cholesterol and are the primary form of cholesterol in the plasma membrane and outside the cell. Cholesteryl esters are made in the endoplasmic reticulum by sterol O-acyltransferase 1 (SOAT1; ACAT1).Cholesteryl ester transfer protein (CETP) controls the flow of cholesterol between two types of lipoprotein particles, which are proteinlipid complexes that move cholesterol between cells. CETP shuttles cholesteryl esters from high-density lipoprotein (HDL) particles to low-density lipoprotein (LDL) particles.Hints of a role for cholesterol transport in AD arose in the 1990s when human genetic studies identified variants of apolipoprotein E (APOE), the protein component of lipoprotein particles, as key genetic risk factors.Together, cholesterol acyltransferase and CETP act to increase cholesterol levels in cardiovascular disease-linked LDL particles and for this reason have been considered good targets for dyslipidemia drugs.Although the precise role of lipoprotein particles in AD pathogenesis is under debate, 3 the new findings "point to the intracellular esterification process" as a targetable space upstream of APOE, said Samuel Gandy, professor of neurology and psychiatry at Mount Sinai School of Medicine. ACAT1 in mouseThe Dartmouth group focused on ACAT1's role in AD and built on earlier findings from Massachusetts General Hospital (MGH) showing that a discontinued cholesterol acyltransferase inhibitor, Pfizer Inc.'s CP-113,818, reduced AD pathology in mice. 4 Team leader Ta-Yuan Chang, professor of biochemistry at Dartmouth, said it has been difficult to study how cholesterol acyltransferase inhibitors improve AD pathology because there are several homologs expressed in different parts of the body. Thus, broad-spectrum inhibitors like CP-113,818 may have multiple effects inside and outside the brain.To get around this problem, Chang's team compared knockouts of the two major murine cholesterol acyltransferases, ACAT1 and ACAT2 (SOAT2). In mouse brain lysates, ACAT1 knockouts showed less enzyme activity than both wild-type mice and ACAT2 knockouts, suggesting that ACAT1 was the most relevant target in AD.The team then made ACAT1 knockout mice that overexpressed human amyloid-β precursor protein (APP), which is converted into toxic β-amyloid (Aβ) peptide fragments that form the characteristic amyloid plaques of AD. ACAT1 knockouts had lower Aβ than wildtype animals that overexpressed APP.Chang's results were published in the Proceedings of the Nationa...

show abstract

Unique Lipoprotein Phenotype and Genotype Associated With Exceptional Longevity

Cited by 528 publications

References 40 publications

Functionally significant insulin-like growth factor I receptor mutations in centenarians

Functionally significant insulin-like growth factor I receptor mutations in centenarians

Association of exceptional parental longevity and physical function in aging

Cholesterol metabolism ADds up

Contact Info

Product

Resources

About