RESUMO
Studies that elucidate why some human tissues age faster than others may shed light on how we age, and ultimately suggest what interventions may be possible. Here we utilize a recent biomarker of aging (referred to as epigenetic clock) to assess the epigenetic ages of up to 30 anatomic sites from supercentenarians (subjects who reached an age of 110 or older) and younger subjects. Using three novel and three published human DNA methylation data sets, we demonstrate that the cerebellum ages more slowly than other parts of the human body. We used both transcriptional data and genetic data to elucidate molecular mechanisms which may explain this finding. The two largest superfamilies of helicases (SF1 and SF2) are significantly over-represented (p=9.2x10-9) among gene transcripts that are over-expressed in the cerebellum compared to other brain regions from the same subject. Furthermore, SNPs that are associated with epigenetic age acceleration in the cerebellum tend to be located near genes from helicase superfamilies SF1 and SF2 (enrichment p=5.8x10-3). Our genetic and transcriptional studies of epigenetic age acceleration support the hypothesis that the slow aging rate of the cerebellum is due to processes that involve RNA helicases.
Assuntos
Idoso de 80 Anos ou mais , Envelhecimento/genética , Cerebelo/fisiologia , Epigênese Genética , RNA Helicases/genética , Adulto , Humanos , Pessoa de Meia-Idade , TranscriptomaRESUMO
Supercentenarians (110 years or older) are the world's oldest people. Seventy four are alive worldwide, with twenty two in the United States. We performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity. We found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in supercentenarian compared to control genomes. We followed up on the gene most enriched for rare protein-altering variants in our cohort of supercentenarians, TSHZ3, by sequencing it in a second cohort of 99 long-lived individuals but did not find a significant enrichment. The genome of one supercentenarian had a pathogenic mutation in DSC2, known to predispose to arrhythmogenic right ventricular cardiomyopathy, which is recommended to be reported to this individual as an incidental finding according to a recent position statement by the American College of Medical Genetics and Genomics. Even with this pathogenic mutation, the proband lived to over 110 years. The entire list of rare protein-altering variants and DNA sequence of all 17 supercentenarian genomes is available as a resource to assist the discovery of the genetic basis of extreme longevity in future studies.
Assuntos
Envelhecimento/genética , Genoma Humano , Longevidade/genética , Idoso de 80 Anos ou mais , Desmocolinas/genética , Feminino , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Masculino , Mutação , Análise de Sequência de DNAAssuntos
Envelhecimento , Geriatria , Rejuvenescimento , História do Século XX , História do Século XXI , Humanos , Estados UnidosRESUMO
For good reason, there is increasing interest in assessing the clinical efficacy of dietary supplements, naturally occurring compounds, and nutraceuticals intended for improving health and reducing disease. This is also a pressing interest in mitigating the effects of age-dependent chronic diseases. This opportunity argues for the need to develop a clear understanding of the basic molecular mechanisms responsible for the actions of dietary biofactors that can contribute to the slowing or preventing of diseases and the possibility of enhancing these improvements by coupling them with healthy lifestyle changes.
