Elevated lipoprotein(a) levels and small apo(a) isoforms are compatible with longevity

Thillet, Joëlle; Doucet, Chantal; Chapman, John; Herbeth, Bernard; Cohen, Daniel; Faure-Delanef, Laurence

doi:10.1016/s0021-9150(97)00217-7

Cited by 52 publications

(31 citation statements)

References 25 publications

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“…Several genes have shown an association with longevity in human populations such as apolipoprotein E, angiotensin converting enzyme, HLA-DR, and lipoprotein(a). [25][26][27][28][29] There was also a reported association with human mitochondrial genotypes. 30 Furthermore, it has been suggested that telomere metabolism may play a role.…”

Section: Discussionmentioning

confidence: 98%

Inheritance of human longevity in Iceland

et al. 2000

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The idea that human longevity is influenced by genetic factors has recently received strong support from work on other species. On the basis of partial population studies and selected kinships, significant correlations between the ages of parents and offspring have been reported, and some but not all twin studies have confirmed that human longevity is moderately inherited. However, studies based upon a relatively small proportion of a population are susceptible to sampling error and selection bias. Here we report the use of a comprehensive population-based computerised genealogy database to examine multigenerational relationships among those who live to the 95th percentile in Iceland. We have developed a clustering tool which can generate large extended pedigrees connecting individuals from any list using the genealogy database. First degree relatives of those living to the 95th percentile are almost twice as likely to live to the 95th percentile compared with controls. Furthermore, we have developed an algorithm which we have named the Minimum Founder Test (MFT) to examine the degree of relatedness of any population-based list of individuals to estimate whether a trait has a familial component. The data indicate that there is a significant genetic component to longevity. In addition, age-specific death rates are significantly lower in the offspring of long-lived parents compared with controls, especially after age 70.

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Section: Discussionmentioning

confidence: 98%

Inheritance of human longevity in Iceland

et al. 2000

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“…35 On the other hand, reports are being accumulated that in the older population, the Lp(a) to apo(a) ratio is significantly increased, pointing toward the possibility that Lp(a)/apo(a) may also have some protective role against life-threatening diseases. 36,37 Such mechanisms may well be connected to angiogenesis, as this latter process favors tumor infiltration and metastasis formation. 38,39 In summary, we have demonstrated herein that human r-apo(a) and the naturally occurring urinary apo(a) fragments affect in vitro tube formation of hMVECs in a fibrin matrix.…”

Section: Discussionmentioning

confidence: 99%

Impact of Apolipoprotein(a) on In Vitro Angiogenesis

Schulter

Koolwijk

Peters

et al. 2001

ATVB

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Abstract-Angiostatin, which consists of the kringle I-IV domains of plasminogen and which is secreted into urine, is an efficient inhibitor of angiogenesis and tumor growth. Because N-terminal apolipoprotein(a) [apo(a)] fragments, which also contain several types of kringle IV domains, are found in urine as well, we evaluated the potential angiostatic properties of these urinary apo(a) fragments and of a recombinant form of apo(a) [r-apo(a)]. We used human microvascular endothelial cell (hMVEC)-based in vitro assays of tube formation in 3-dimensional fibrin matrixes. Purified urinary apo(a) fragments or r-apo(a) inhibited the basic fibroblast growth factor/tumor necrosis factor-␣-induced formation of capillary-like structures. At concentrations varying from 0.2 to 10 g/mL, urinary apo(a) fragments inhibited tube formation by as much as 70%, whereas there was complete inhibition by r-apo(a). The highest concentrations of both inhibitors also reduced urokinase plasminogen activator production of basic fibroblast growth factor-induced hMVEC proliferation. The inhibitors had no effect on plasminogen activator inhibitor-1 expression. If our in vitro model for angiogenesis is valid for the in vivo situation as well, our data point toward the possibility that apo(a) may also be physiologically operative in modulating angiogenesis, as the concentration of free apo(a) found in humans exceeds that tested herein.

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“…A previously unfavorable LPA genotype has been reported to be paradoxically increased in French and Italian studies of centenarians [26][27][28], representing an increased frequency of disease genotype in centenarians. Our results suggest that a harmful genotype probably does not turn into a protective one, but rather indicates a protection by other favorable longevity genotypes.…”

Section: Discussionmentioning

confidence: 99%

“…As the population approaches extreme longevity, the initial decline should reverse, and the prevalence of the deleterious genotype should increase. Indeed, studies in French and Italian centenarian subjects [26][27][28] reported the paradox of an unfavorable genotype and phenotype that are more common in centenarians. Among the set of genes tested, we have identified two such genes: one is LPA (see Figure 3), which is associated with increased risk for vascular diseases in the elderly [29].…”

Section: Identifying Buffered Age-related Disease Genesmentioning

confidence: 99%

Buffering Mechanisms in Aging: A systems approach towards uncovering the genetic component of aging

Bergman

Atzmon

et al. 2005

PLoS Comput Biol

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An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the ''oldest old'' Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows diseaserelated genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidatebuffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.

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Elevated lipoprotein(a) levels and small apo(a) isoforms are compatible with longevity

Cited by 52 publications

References 25 publications

Inheritance of human longevity in Iceland

Inheritance of human longevity in Iceland

Impact of Apolipoprotein(a) on In Vitro Angiogenesis

Buffering Mechanisms in Aging: A systems approach towards uncovering the genetic component of aging

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