Genetic Predisposition to Disease

Publication Title: 
PloS One

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls.

Author(s): 
Sebastiani, Paola
Solovieff, Nadia
Dewan, Andrew T.
Walsh, Kyle M.
Puca, Annibale
Hartley, Stephen W.
Melista, Efthymia
Andersen, Stacy
Dworkis, Daniel A.
Wilk, Jemma B.
Myers, Richard H.
Steinberg, Martin H.
Montano, Monty
Baldwin, Clinton T.
Hoh, Josephine
Perls, Thomas T.
Publication Title: 
The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences

Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date.

Author(s): 
Murabito, Joanne M.
Yuan, Rong
Lunetta, Kathryn L.
Publication Title: 
Neurobiology of Aging

Exceptional longevity is associated with substantial heritability. The ?4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ?2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership.

Author(s): 
Schupf, Nicole
Barral, Sandra
Perls, Thomas
Newman, Anne
Christensen, Kaare
Thyagarajan, Bharat
Province, Michael
Rossi, Winifred K.
Mayeux, Richard
Publication Title: 
Stroke; a Journal of Cerebral Circulation

BACKGROUND AND PURPOSE: On MRI, cerebral white matter lesions, lacunar infarcts, and cerebral microbleeds are common imaging correlates of cerebral small vessel damage in apparently healthy elderly individuals. We investigated whether middle-aged to elderly offspring of nonagenarian siblings, who are predisposed to become long-lived as well, have a lower prevalence of white matter lesions, lacunar infarcts, and cerebral microbleeds than control subjects. METHODS: All subjects were from the Leiden Longevity Study.

Author(s): 
Altmann-Schneider, Irmhild
van der Grond, Jeroen
Slagboom, P. Eline
Westendorp, Rudi G. J.
Maier, Andrea B.
van Buchem, Mark A.
de Craen, Anton J. M.
Publication Title: 
Lipids in Health and Disease

BACKGROUND: The -493G/T polymorphism in the microsomal triglyceride transfer protein (MTP) gene is associated with lower serum low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and longevity in several populations, but the results are inconsistent in different racial/ethnic groups. The current study was to investigate the plausible association of MTP -493G/T polymorphism with serum lipid levels and longevity in Zhuang long-lived families residing in Bama area, a famous home of longevity in Guangxi, China.

Author(s): 
Pan, Shang-Ling
Luo, Xiao-Qiu
Lu, Ze-Ping
Lu, Shao-Hua
Luo, Huan
Liu, Cheng-Wu
Hu, Cai-You
Yang, Ming
Du, Li-Li
Song, Zhen
Pang, Guo-Fang
Wu, Hua-Yu
Huang, Jin-Bo
Peng, Jun-hua
Yin, Rui-Xing
Publication Title: 
Age (Dordrecht, Netherlands)

The myostatin (MSTN) gene is a candidate to influence extreme longevity owing to its role in modulating muscle mass and sarcopenia and especially in inhibiting the main nutrient-sensing pathway involved in longevity, i.e. mammalian target of rapamycin. We compared allele/genotype distributions of the exonic MSTN variants K153R (rs1805086), E164K (rs35781413), I225T and P198A, in Spanish centenarians (cases, n = 156; 132 women, age range 100-111 years) and younger adults (controls, n = 384; 167 women, age <50 years).

Author(s): 
Garatachea, Nuria
PinÛs, Tom‡s
C·mara, Yolanda
RodrÌguez-Romo, Gabriel
Emanuele, Enzo
Ricevuti, Giovanni
Venturini, Letizia
Santos-Lozano, Alejandro
Santiago-Dorrego, Catalina
Fiuza-Luces, Carmen
Yvert, Thomas
Andreu, Antoni L.
Lucia, Alejandro
Publication Title: 
JAMA neurology

IMPORTANCE: Family studies of centenarians and long-lived persons have found substantial familial aggregation of survival to extreme ages; however, the extent to which such familial longevity is characterized by cognitively intact survival is not established. OBJECTIVE: To determine whether families with exceptional longevity are protected against cognitive impairment consistent with Alzheimer disease. DESIGN: Cross-sectional analysis. SETTING: Multisite study in New York, Massachusetts, Pennsylvania, and Denmark.

Author(s): 
Cosentino, Stephanie
Schupf, Nicole
Christensen, Kaare
Andersen, Stacy L.
Newman, Anne
Mayeux, Richard
Publication Title: 
MÈdecine Sciences: M/S

Most of the signalling pathways involved in aging regulation have been recently found well conserved at various levels throughout the evolution. Taking this into account, a diversity of model organisms, including worms, rodents, and lemurs as well, allows to address different questions: how to understand the interactions between genetic and environmental factors while challenging theories of aging, to preserve hearing integrity, to fight against senescence of neural stem cells, or to explore brain fitness from gene expression to cognitive and social behavior?

Author(s): 
Galas, Simon
Ch‚teau, Marie-ThÈrËse
PomiËs, Pascal
Wang, Jing
Menardo, Julien
Puel, Jean-Luc
Hugnot, Jean-Philippe
Verdier, Jean-Michel
Devau, Gina
Publication Title: 
Biochemical Society Transactions

Although there is general agreement that most forms of common disease develop as a consequence of a combination of factors, including genetic, environmental and behavioural contributors, the actual mechanistic basis of how these factors initiate or promote diabetes, cancer, neurodegenerative and cardiovascular diseases in some individuals but not in others with seemingly identical risk factor profiles, is not clearly understood.

Author(s): 
Ballinger, Scott W.
Publication Title: 
Oncotarget

It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the "hyperfunction theory", which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin). These pathways consist of different enzymes, mostly kinases, but also phosphatases, deacetylases, GTPases, and some other molecules that cause overactivation of normal cellular functions.

Author(s): 
Berman, Albert E.
Leontieva, Olga V.
Natarajan, Venkatesh
McCubrey, James A.
Demidenko, Zoya N.
Nikiforov, Mikhail A.

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