Mitochondrial DNA involvement in human longevity

AbstractThe main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future

Pai Hsien-yung, Crystal Boys and Taipei's Memories : View from 'Metropolis Spaces' of the 1970s(Summaries : International Symposium "People's Transportation and Cultural Diversity in East Asia")

Genetic signatures from the Paleolithic inhabitants of Eurasia can be traced from the early divergent mitochondrial DNA lineages still present in contemporary human populations. Previous studies already suggested a pre-Neolithic diffusion of mitochondrial haplogroup HV*(xH,V) lineages, a relatively rare class of mtDNA types that includes parallel branches mainly distributed across Europe and West Asia with a certain degree of structure. Up till now, variation within haplogroup HV was addressed mainly by analyzing sequence data from the mtDNA control region, except for specific sub-branches, such as HV4 or the widely distributed haplogroups H and V. In this study, we present a revised HV topology based on full mtDNA genome data, and we include a comprehensive dataset consisting of 316 complete mtDNA sequences including 60 new samples from the Italian peninsula, a previously underrepresented geographic area. We highlight points of instability in the particular topology of this haplogroup, reconstructed with BEAST-generated trees and networks. We also confirm a major lineage expansion that probably followed the Late Glacial Maximum and preceded Neolithic population movements. We finally observe that Italy harbors a reservoir of mtDNA diversity, with deep-rooting HV lineages often related to sequences present in the Caucasus and the Middle East. The resulting hypothesis of a glacial refugium in Southern Italy has implications for the understanding of late Paleolithic population movements and is discussed within the archaeological cultural shifts occurred over the entire continent

Somatic Point Mutations in mtDNA Control Region Are Influenced by Genetic Background and Associated with Healthy Aging: A GEHA Study

Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate control region somatic heteroplasmy in the elderly, we analyzed the segment surrounding the nt 150 position (previously reported as specific of Leukocytes) in various types of leukocytes obtained from 195 ultra-nonagenarians sib-pairs of Italian or Finnish origin collected in the frame of the GEHA Project. We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions

Optimization of whole mitochondrial genome sequencing with Ion Personal Genome Machine (PGM) System.

The human mitochondrial DNA (mtDNA) phylogeny is an almost perfect molecular prototype for a non-recombining locus and knowledge on its variation has been extensively used in molecular anthropology and population genetics studies. Furthermore, its mode of inheritance, high mutation rate and high cellular copy number make this locus a primary choice also in the field of ancient DNA analysis, as well as in different contest such as biomedical research and diagnostic of mitochondrial disorders or human identification for forensic purposes. In the very last years, the study of mtDNA control region sequence and coding region single nucleotide polymorphisms have been gradually substituted by the investigation of variation at the whole mitochondrial genome, allowing analyses at a much higher resolution level and a deeper discrimination between haplogroups. In fact, high-throughput sequencing of whole mitochondrial genomes is now possible with lower costs with respect to those related to the traditional Sanger method thanks to Next Generation Sequencing (NGS) technologies. Among them, the Ion Personal Genome Machine (PGM, Life Technologies) is a new platform that uses an innovative method of sequencing. In fact, it does not use fluorescence or chemiluminescence, but measures the proton (H+) ions released during base incorporation. This new sequencing method allows to reduce times and costs of sequencing. The workflow, like other NGS, consists of four major steps: library construction, template preparation, sequencing and analysis. We develop a workflow for processing multiple samples in parallel through the preparation of barcoded libraries obtained by physical fragmentation of two long range PCR products with Bioruptor sonication system (Diagenode) at 200 base pairs reads. After equalization of single barcoded libraries in a pool the samples are subjected to an emulsion PCR reaction step. In this step, the library are attached to beads and amplified. During a step of enrichment only the beads that bind amplified template fragments are retrieved and these will be the template for the sequencing reaction. The sequencing technology is what really differentiates Ion Torrent platform; since optics are not required, the sequencing reaction is relatively fast and inexpensive. The obtained sequences are processed and aligned to the reference genome by means of the Ion Torrent suite and a dedicated bioinformatics tool was used to call single nucleotide and small insertion/deletion variants. We compared our results with those obtained by processing raw data via an ad hoc developed pipeline, as well as with those resulting from Sanger sequencing of the same samples to assess the reliability of the adopted protocol and sequencing technology

Circulating miR-122-5p, miR-92a-3p, and miR-18a-5p as Potential Biomarkers in Human Liver Transplantation Follow-Up

The requirement of blood-circulating sensitive biomarkers for monitoring liver transplant (LT) is currently a necessary step aiming at the reduction of standard invasive protocols, such as liver biopsy. In this respect, the main objective of this study is to assess circulating microRNA (c-miR) changes in recipients’ blood before and after LT and to correlate their blood levels with gold standard biomarkers and with outcomes such as rejection or complications after graft. An miR profile was initially performed; then, the most deregulated miRs were validated by RT-qPCR in 14 recipients pre- and post-LT and compared to a control group of 24 nontransplanted healthy subjects. MiR-122-5p, miR-92a-3p, miR-18a-5p, and miR-30c-5p, identified in the validation phase, were also analyzed considering an additional 19 serum samples collected from LT recipients and focusing on different follow-up (FU) times. The results showed significant, FU-related changes in c-miRs. In particular, miR-122-5p, miR-92a-3p, and miR-18a-5p revealed the same trend after transplantation and an increase in their level was found in patients with complications, independently from FU times. Conversely, the variations in the standard haemato-biochemical parameters for liver function assessment were not significant in the same FU period, confirming the importance of c-miRs as potential noninvasive biomarkers for monitoring patients’ outcomes

Circulating miR-122-5p, miR-92a-3p, and miR-18a-5p as Potential Biomarkers in Human Liver Transplantation Follow-Up

The requirement of blood-circulating sensitive biomarkers for monitoring liver transplant (LT) is currently a necessary step aiming at the reduction of standard invasive protocols, such as liver biopsy. In this respect, the main objective of this study is to assess circulating microRNA (c-miR) changes in recipients’ blood before and after LT and to correlate their blood levels with gold standard biomarkers and with outcomes such as rejection or complications after graft. An miR profile was initially performed; then, the most deregulated miRs were validated by RT-qPCR in 14 recipients pre- and post-LT and compared to a control group of 24 nontransplanted healthy subjects. MiR-122-5p, miR-92a-3p, miR-18a-5p, and miR-30c-5p, identified in the validation phase, were also analyzed considering an additional 19 serum samples collected from LT recipients and focusing on different follow-up (FU) times. The results showed significant, FU-related changes in c-miRs. In particular, miR-122-5p, miR-92a-3p, and miR-18a-5p revealed the same trend after transplantation and an increase in their level was found in patients with complications, independently from FU times. Conversely, the variations in the standard haemato-biochemical parameters for liver function assessment were not significant in the same FU period, confirming the importance of c-miRs as potential noninvasive biomarkers for monitoring patients’ outcomes

Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans.

lavoro originale sull'invecchiamento uman