The Journal of Clinical Endocrinology and Metabolism
Aging is a natural process that involves a general decline in many physiological functions, resulting in loss of function and eventually death. Extensive research is being performed in order to elucidate the biology of aging, especially with the advent of newer molecular and genetic methodologies. The endocrine system plays a major role in orchestrating cellular interactions, metabolism, growth, and senescence. Thus, researchers traditionally used hormones as tools to induce and examine specific biological effects that are associated with aging.
The PTPN22 gene, located on chromosome 1p13, encoding lymphoid protein tyrosine phosphatase (LYP), plays a crucial role in the negative control of T lymphocyte activation. Since the age-related change in T-cell signal transduction may be one of the most important causes of cell-mediated immune response decline with ageing, we performed a population-based association study to test whether the PTPN22 1858C>T (R620W) functional polymorphism affects the ability to survive to old age and to reach even exceptional life expectancy.
Our study purpose was to compare a disease-related polygenic profile that combined a total of 62 genetic variants among (i) people reaching exceptional longevity, i.e., centenarians (n = 54, 100-108 years, 48 women) and (ii) ethnically matched healthy controls (n = 87, 19-43 years, 47 women).
Leukocyte telomere length is widely considered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also positively associated with several measures of healthy aging, but this relationship was dependent on age.
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.
The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
The single nucleotide polymorphism, rs2866164, in the MTP gene, has been associated with human longevity but has not been validated by subsequent longevity studies. Using our population of Ashkenazi Jews, we find that the MTP CC genotype is significantly overrepresented in centenarians and their offspring, as compared with controls (p < .05). However, when we examined MTP CC genotype frequency pattern with aging, we observed a monotonic decline between ages 55-85 years followed by a dramatic enrichment after age 90 years, forming a U-shape pattern (p < .05).
Longevity phenotype in humans results from the influence of environmental and genetic factors. Few gene polymorphisms have been identified so far with a modest effect on lifespan leaving room for the search of other players in the longevity game. It has been recently demonstrated that targeted disruption of the mouse homolog of the human angiotensin II type 1 receptor (AT1R) gene (AGTR1) translates into marked prolongation of animal lifespan (Benigni et al., J Clin Invest 119(3):524-530, 2009).
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).
Despite evidence of a substantial genetic component, the genetic factors that underlie longevity in humans remain to be identified. Previous genome-wide linkage and association studies have not found strong evidence for the contribution of common variants besides the APOE gene, suggesting the role of rare variants in human longevity. To discover rare variants that might contribute to longevity, we selected 988 candidate genes and performed a pilot study to identify novel non-synonymous variants in 6 Ashkenazi Jewish centenarians older than 105.
Single nucleotide polymorphisms of angiotensin-converting enzyme (ACE) such as rs1799752, nuclear factor kappa B (NFkB) such as rs28362491 and cholesteryl ester transport protein (CETP) such as rs708272 (TaqB1) and rs5882 (I405V) were evaluated in nonagenarians, centenarians, and average life span individuals (controls). The study population (n = 307; 190 nonagenarians, 12 centenarians and 105 middle-aged controls) was genotyped for ACE, NFkB, and CETP genetic variants.