Genetic Analysis of TOR Complex Gene Variation With Human Longevity: A Nested Case-Control Study of American Men of Japanese Ancestry

Brian J. Morris, Timothy A. Donlon, Qimei He, John S. Grove, Kamal H. Masaki, Ayako Elliott, D. Craig Willcox, Richard Allsopp, and Bradley J. Willcox conducted a study to test the association of tagging single-nucleotide polymorphisms with human longevity. The study focused on capturing genetic variation across key TOR complex 1 (TORC1) and TOR complex 2 (TORC2) genes MToR, RPToR, and RicToR and the important downstream effector gene RPS6Ka1. The subjects of the study were a homogeneous population of American men of Japanese ancestry who were well-characterized for aging phenotypes and had been followed for 48 years. The study used a nested case-control design involving 440 subjects aged 95 years and older and 374 controls.

The study found no association between six tagging single-nucleotide polymorphisms for MToR, 61 for RPToR, seven for RicToR, or five for RPS6Ka1 with longevity. Of the 40 aging-related phenotypes studied, no significant association with genotype was found. Therefore, the common genetic variation (minor allele frequency 10%) in MToR, RPToR, RicToR, and RPS6Ka1 is not associated with extreme old age or aging phenotypes in this population.

Further research is needed to assess the potential genetic contribution of other mTOR pathway genes to human longevity, gene expression, upstream and downstream targets, and clinically relevant aging phenotypes.

Keywords: Genetic association analysisHealth spanLife spanLongevityTarget of rapamycin.

Received November 13, 2013; accepted January 20, 2014

Decision editor: Rafael de Cabo, PhD

Nutrient-sensing pathways (7,8) are pivotal to life span extension in response to caloric restriction (9,10). Despite good evidence showing that insulin/insulin-like growth factor-1 and mTOR pathways are critical for life span regulation of model organisms (6,11,12), to date, attainment of extreme old age in humans has been consistently replicated only for variation in one gene in these pathways, the forkhead box O transcription factor 3 gene (FoXo3) (5,6).

Major causes of death in developed countries are influenced by environmental and genetic factors. Identification of the molecular mechanisms responsible for this complex polygenic phenotype represents a major current challenge. Because the genetic component becomes paramount for the attainment of extreme old age (13), studies of polymorphisms in genes belonging to intracellular pathways that are modulated by caloric restriction have been conducted in nonagenarian and centenarian populations (4,5). These pathways affect insulin/insulin-like growth factor-1 signaling and growth responses. The hyperfunction theory of aging postulates that in later life, the once-beneficial processes contributing to growth become deleterious by causing hypertrophic and hyperplastic pathologies (6).

mTOR is an evolutionarily conserved serine/threonine phosphoinositide 3-kinase-related kinase with crucial roles in cell growth and metabolism in response to nutrients, growth factors, cellular energy, and stress (6,8,13,14). Rapamycin forms a stoichiometric complex with mTOR to inhibit its kinase activity (15,16) and can thus extend mean and maximum lifespan of middle-aged male and female mice with no adverse health consequences but only benefits.

The mechanistic (formerly mammalian) target of rapamycin (mTOR) is positioned at a central hub of nutrient-sensing pathways and is pivotal to lifespan determination in model organisms. mTOR is a component of two structurally and functionally distinct multiprotein complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). In mammals, two accessory proteins, regulatory-associated protein of mTOR (raptor or RPTOR) and rapamycin-insensitive companion of mTOR (rictor or RICTOR), distinguish TORC1 from TORC2, respectively (19,20). mTORC1 exerts its effects on temporal control of cell growth by regulating several cellular processes, including translation, transcription, ribosome biogenesis, nutrient transport, and autophagy (14). The two TOR complexes constitute an evolutionarily conserved ancestral signaling network that responds to energy levels and sources of energy to control the fundamental process of cell growth and maintenance. In addition to its key role in aging, mTOR has been implicated in cancer, cardiovascular disease, obesity, and diabetes (21).

The present study used cases (longevity phenotype) defined as HHP and HAAS participants who had survived beyond the upper 1% of theControls who died up to the age of 81 years (mean age at death = 78.1 ± 1.8 SD years [range: 73-81 years]), consistent with the 3.5 years longer life expectancy of Japanese American men in Hawaii (29). Analyses showed no evidence of population stratification in the dataset (5). All participants were drawn from records of study participants updated up to June 2011. Archived phenotypic data and blood samples from Examination 4 of the HHP (1991-1993), which coincided with the commencement of the HAAS, were used as the baseline exam for this nested case-control study. We had phenotype data for only 439 cases because one subject did not attend Exam 4. Participants included 3,734 men aged 71-93 years at Exam 4 (mean age: 77.9 ± 4.7 years), representing approximately 80% of the survivors from the original HHP (30). Procedures performed were in accordance with institutional guidelines and were approved by the Institutional Review Board of Kuakini Medical Center. Written informed consent was obtained from all study participants or from family representatives, if participants could not provide consent.