Genetic studies reveal the role of the endocrine and metabolic systems in aging

Abstract

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. Furthermore, because our recent knowledge on hormonal action expanded significantly, downstream pathways and genetic determinants currently prevail in aging research. In this review, we will summarize the effects of several hormones on human aging and longevity and present recent data from the Longevity Genes Study performed at Albert Einstein College of Medicine, looking at the phenotype and genotype of centenarians and their offspring. We will demonstrate that genetic factors that are associated with human longevity are heritable and may contribute not only to quantitative longevity but also to protection from age-dependent disease and exceptional good health.

Trial registration: ClinicalTrials.gov NCT00707694.

Figure 1

Possibilities for changes in frequency of a functional genotype with age. Green line represents “Longevity genes”—genotype in a gene that contributes to longevity and protection against some age-related diseases. Red line represents “Killing-genes”—the relative prevalence of deleterious genotypes in genes associated with age-related diseases decreases as the population ages, as mortality reduces the proportion of individuals carrying this deleterious genotype. Black line represents the majority of the genes with SNPs whose frequency is not changing with aging in this cross-sectional analysis.

Figure 2

The basal frequency and trends of favorable longevity genotypes with aging. APOC-3, Genotype apolipoprotein C-3; CETP, homozygosity genotype in cholesterol ester transfer protein; ADIPOQ, del/del deletion homozygosity in the 3″ untranslated region adiponectin gene; FOXO3A, T genotypes in the FOXO 3A gene; TSH-R, genotypes in the TSH receptor gene; and IGF-IR, genotypes in the IGF-IR gene.

Figure 3

Manhattan plot of GWAS of Ashkenazi Jewish centenarians and controls. GWAS of 364 centenarians and 251 controls (about 70 yr of age, from the same geographical area and the same ethnic background), using Affymetrix 6.0 genome-wide chips. The chips contain probes for 906,600 SNPs and 946,000 CNVs. The resulting data set includes (complying with institutional review board specifications) age, gender, SNP, and CNV genotype results as well as results from the statistical analysis. The GWAS data on SNPs are visualized in the form of a Manhattan plot, with each dot indicating a different variant (with chromosomes colored). The SNPs of genome-wide significance form Bonferroni-corrected peaks with P value < 10⁻⁷.