Cardiovascular Disease Delay in Centenarian Offspring: Role of Heat Shock Proteins

Terry, Dellara F.; McCormick, Maegan A; Andersen, Stacy L.; Pennington, JaeMi; Schoenhofen, Emily A.; Palaima, Elizabeth; Bausero, María A.; Ogawa, Kishiko; Perls, Thomas T.; Asea, Alexzander

doi:10.1196/annals.1297.092

Cited by 61 publications

(35 citation statements)

References 11 publications

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“…In conclusion, this study confirms the results of our pilot study of serum Hsp70 levels in centenarian offspring compared to controls (Terry et al, 2004) and those of Rea at al (Rea et al, 2001) and Jin et al (Jin et al, 2004), showing that serum Hsp70 levels are lower in those individuals that reach an advanced age. In addition, it suggests that low serum Hsp70 levels are associated with longevity independent of other covariates such as age, gender, race, income, alcohol, cardiovascular disease, and a variety of other age-related diseases.…”

Section: Discussionsupporting

confidence: 80%

Serum heat shock protein 70 level as a biomarker of exceptional longevity

Terry

Wyszynski

Nolan

et al. 2006

Mechanisms of Ageing and Development

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Heat shock proteins are highly conserved proteins that, when produced intracellularly, protect stress exposed cells. In contrast, extracellular Hsp70 has been shown to have both protective and deleterious effects. In this study, we assessed heat shock protein 70 (Hsp70) for its potential role in human longevity. Because of the importance of HSP to disease processes, cellular protection, and inflammation, we hypothesized that: (1) Hsp70 levels in centenarians and centenarian offspring are different from controls and (2) alleles in genes associated with Hsp70 explain these differences. In this cross-sectional study, we assessed serum Hsp70 levels from participants enrolled in either the New England Centenarian Study (NECS) or the Longevity Genes Project (LGP): 87 centenarians (from LGP), 93 centenarian offspring (from NECS), and 126 controls (43 from NECS, 83 from LGP). We also examined genotypic and allelic frequencies of polymorphisms in HSP70-A1A and HSP70-A1B in 347 centenarians (266 from the NECS, 81 from the LGP), 260 NECS centenarian offspring, and 238 controls (NECS: 53 spousal controls and 106 septuagenarian offspring controls; LGP: 79 spousal controls). The adjusted mean serum Hsp70 levels (ng/mL) for the NECS centenarian offspring, LGP centenarians, LGP spousal controls, and NECS controls were 1.05, 1.13, 3.05, 6.93, respectively, suggesting that a low serum Hsp70 level is associated with longevity; however, no genetic associations were found with two SNPs within two hsp70 genes.

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Section: Discussionsupporting

confidence: 80%

Serum heat shock protein 70 level as a biomarker of exceptional longevity

Terry

Wyszynski

Nolan

et al. 2006

Mechanisms of Ageing and Development

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“…As a first step, we must consider the protective effect that longevity genes might confer and what effect this might have on lifespan. It has been shown that offspring of centenarians are healthier than their appropriate agematched controls, supporting the notion of inheritance from centenarians to their offspring [10,12,[16][17][18][19][20]. This observation lends support to the hypothesis that longevity genes might buffer the deleterious effect of certain genetically determined age-related diseases.…”

Section: Identification and The Interpretation Of A U-shape Pattern Osupporting

confidence: 68%

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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“…Extracellular Hsp70 (increased serum levels) is evident in a variety of clinical scenarios associated with physiologic stress. For example, increased extracellular Hsp70 levels are noted following strenuous exercise (180,181,(204)(205)(206)(207)(208), following cardio-pulmonary bypass in both adults (209,210) and children (Wheeler, unpublished data), in elderly adults (211,212), and in children with acute lung injury (Wheeler, unpublished data). In addition, increased extracellular Hsp70 concentrations correlate with worse outcome in a variety of inflammatory disease processes, including liver disease (213), coronary artery disease (214)(215)(216)(217), traumatic brain injury secondary to child abuse (218), pre-eclampsia (219), sickle cell disease vasoocclusive crisis (220), septic shock (221), and traumatic brain injury (222).…”

Section: Stress Proteins and Innate Immunitymentioning

confidence: 99%

Heat shock response and acute lung injury☆

Wheeler

Wong

2007

Free Radical Biology and Medicine

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All cells respond to stress through the activation of primitive, evolutionarily conserved genetic programs that maintain homeostasis and assure cell survival. Stress adaptation, which is known in the literature by a myriad of terms, including tolerance, desensitization, conditioning, and reprogramming, is a common paradigm found throughout nature, in which a primary exposure of a cell or organism to a stressful stimulus (e.g., heat) results in an adaptive response by which a second exposure to the same stimulus produces a minimal response. More interesting is the phenomenon of cross-tolerance, by which a primary exposure to a stressful stimulus results in an adaptive response whereby the cell or organism is resistant to a subsequent stress that is different from the initial stress (i.e. exposure to heat stress leading to resistance to oxidant stress). The heat shock response is one of the more commonly described examples of stress adaptation and is characterized by the rapid expression of a unique group of proteins collectively known as heat shock proteins (also commonly referred to as stress proteins). The expression of heat shock proteins is well described in both whole lungs and in specific lung cells from a variety of species and in response to a variety of stressors. More importantly, in vitro data, as well as data from various animal models of acute lung injury, demonstrate that heat shock proteins, especially Hsp27, Hsp32, Hsp60, and Hsp70 have an important cytoprotective role during lung inflammation and injury.

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Cardiovascular Disease Delay in Centenarian Offspring: Role of Heat Shock Proteins

Cited by 61 publications

References 11 publications

Serum heat shock protein 70 level as a biomarker of exceptional longevity

Serum heat shock protein 70 level as a biomarker of exceptional longevity

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

Heat shock response and acute lung injury☆

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