The impact of mitochondrial DNA on human lifespan: a view from studies on centenarians

The role of inherited and somatic mutations of mitochondrial DNA (mtDNA) in aging and longevity is complex and highly controversial, owing to its peculiar genetics, including the phenomenon of heteroplasmy. Most of the data on mtDNA and longevity have been obtained on humans and particularly on centenarians, i. e., people who escaped or delayed the major age-related pathologies and reached the extreme limit of human lifespan. In this review we summarize the most recent advances in this field that suggest a consistent role in human longevity of both germ-line inherited and somatically acquired mutations. The particular case of the association with longevity of the somatic C150T mutation is extensively discussed, challenging the tenet that mtDNA mutations are basically detrimental. We also stress several limitations of our present knowledge, regarding the difficulty in extrapolating to humans the results obtained in animal models, owing to a variety of biological differences, including the very limited genetic variability of mtDNA in the strains used in laboratory experiments. The use of high-throughput technologies and the extensive analysis, possibly at the single cell level, of different tissues and cell types derived from the same individual will help in disentangling the complexity of mtDNA in aging and longevity.     

Ca2+-activated K+ channels of human and rabbit erythrocytes display distinctive patterns of inhibition by venom peptide toxins

Despite recent progress in the molecular characterization of high-conductance Ca²⁺-activated K⁺ (maxi-K) channels, the molecular identities of intermediate conductance Ca²⁺-activated K⁺ channels, including that of mature erythrocytes, remains unknown. We have used various peptide toxins to characterize the intermediate conductance Ca²⁺-activated K⁺ channels (Gardos pathway) of human and rabbit red cells. With studies on K⁺ transport and on binding of ¹²⁵I-charybdotoxin (ChTX) and ¹²⁵I-kaliotoxin (KTX) binding in red cells, we provide evidence for the distinct nature of the red cell Gardos channel among described Ca²⁺-activated K⁺ channels based on (i) the characteristic inhibition and binding patterns produced by ChTX analogues, iberiotoxin (IbTX) and IbTX-like ChTX mutants, and KTX (1–37 and 1–38 variants); (ii) the presence of some properties heretofore attributed only to voltage-gated channels, including inhibition of K transport by margatoxin (MgTX) and by stichodactyla toxin (StK); (iii) and the ability of scyllatoxin (ScyTX) and apamin to displace bound ¹²⁵I-charybdotoxin, a novel property for K⁺ channels. These unusual pharmacological characteristics suggest a unique structure for the red cell Gardos channel.We thank Dr. Chris Miller of Brandeis University for generously providing recombinant ChTX mutants, Dr. Maria Garcia of Merck Research Laboratories for MgTX and Dr. Regine Romi of Laboratoire d'Ingenierie des Proteines (Marseille, France) for synthetic KTX,1–37 and KTX,1–38. This research was supported by grant HL-15157 from the National Institutes of Health.     

Ulminium diluviale Unger : historique de la découverte et nouvelle étude

A fossil tree was discovered during the 16th century at Jáchymov (Bohemia). The wood was first named by Unger, in 1842, Ulminium diluviale. But it belongs to the Lauraceae family and Felix, in 1883, named it Laurinoxylon diluviale. The authors give the history and the geological setting of the area and describe the anatomy of the wood. The diagnosis of the genus Laurinoxylon Felix, 1883. is emended as follows: heteroxylous fossil wood with average sized solitary vessels or in radial groups; perforation plates simple and sometimes scalariform; intervascular pits alternate and moderately large; thyloses present. Paratracheal parenchyma. Uni to five seriate rays, slightly heterocellular and less than 1 mm high; ray-vessel pits large often stretched. Libriform or with radial pits fibres. Oil cells or mucilage (idioblasts) present. The diagnosis of the species Laurinoxylon diluviale (Unger) Felix, 1883. is also emended. Heteroxylous fossil wood with distinct growth rings; late wood poorly developed with vessels of diameter distinctly smaller as compared to the early wood and with smaller diameter fibres. Diffuse to semiporous vessels, solitary or in radial groups of two to seven , nine to 16 pores/mm²; tangential diameter 100 to 154 μm in early wood and 44 to 72 μm in late wood; vessel length 300 to 550 μm; perforation plates simple and scalariforme (6–12 bars); intervascular pits alternate, rounded (diameter 7–10 μm) or elliptic (long axes × short axes: 10–15 μm × 7–10 μm); thylosis present. Paratracheal parenchyma in more or less complete rows (1–2 cells wide) around the vessels. Heterocellular rays (1–(3) rows of upright cells), of one to five, more frequently three to four cells wide (80%); two to 36 cells high (60 to 820 μm); six to seven rays per tangential millimetre; vessels-rays pits sometimes large, stretched horizontally to vertically. Fibres of 15 to 25 μm in diameter; cell walls of 2–3 μm thick; pits not seen. Oil cells (idioblasts) at the ray margins; 27–60 μm in tangential diameter; 50–80 μm in radial diameter; 72–140 μm high; density of zero to 18 per transversal square millimetres depending on the observed area.     

Structural basis of the ribosomal machinery for peptide bond formation,translocation, and nascent chain progression

Crystal structures of tRNA mimics complexed with the large ribosomal subunit of Deinococcus radiodurans indicate that remote interactions determine the precise orientation of tRNA in the peptidyl-transferase center (PTC). The PTC tolerates various orientations of puromycin derivatives and its flexibility allows the conformational rearrangements required for peptide-bond formation. Sparsomycin binds to A2602 and alters the PTC conformation. H69, the intersubunit-bridge connecting the PTC and decoding site, may also participate in tRNA placement and translocation. A spiral rotation of the 3' end of the A-site tRNA around a 2-fold axis of symmetry identified within the PTC suggests a unified ribosomal machinery for peptide-bond formation, A-to-P-site translocation, and entrance of nascent proteins into the exit tunnel. Similar 2-fold related regions, detected in all known structures of large ribosomal subunits, indicate the universality of this mechanism.     

Innate immunity and inflammation in ageing: a key for understanding age-related diseases

The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for age-related chronic diseases. Alzheimer's disease, atherosclerosis, diabetes and even sarcopenia and cancer, just to mention a few – have an important inflammatory component, though disease progression seems also dependent on the genetic background of individuals. Emerging evidence suggests that pro-inflammatory genotypes are related to unsuccessful ageing, and, reciprocally, controlling inflammatory status may allow a better chance of successful ageing. In other words, age-related diseases are "the price we pay" for a life-long active immune system: this system has also the potential to harm us later, as its fine tuning becomes compromised. Our immune system has evolved to control pathogens, so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections with pathogens aggressively. Thus, inflammatory genotypes are an important and necessary part of the normal host responses to pathogens in early life, but the overproduction of inflammatory molecules might also cause immune-related inflammatory diseases and eventually death later. Therefore, low responder genotypes involved in regulation of innate defence mechanisms, might better control inflammatory responses and age-related disease development, resulting in an increased chance of long life survival in a "permissive" environment with reduced pathogen load, medical care and increased quality of life.     

Genomic characterization of self-incompatibility ribonucleases in the Central Asian pear germplasm and introgression of new alleles from other species of the genus Pyrus

The Pyrus species exhibit the so-called S-RNase-based gametophytic self-incompatibility system, which is considered to be the most widespread self-incompatibility system among flowering plants. In this study, 57 Iranian pear (Pyrus communis L.) domestic cultivars and wild genotypes, plus 21 European pear cultivars used as references, were genotyped adopting a PCR-based genotyping assay using consensus and allele-specific primers. The results revealed traces of significant genetic contribution in the Iranian traditional varieties and genotypes from other Pyrus species; the genetic contribution of Japanese pear clearly emerged with the detection of some Pyrus pyrifolia S-RNase alleles. Moreover, our results highlighted the presence of three new S-RNase alleles (named S₁₂₆, S₁₂₇, and S₁₂₈) that were not previously identified in P. communis, possibly introduced in the germplasm of cultivated pear through gene transfer from other cultivated or wild species.     

Pathophysiology of ageing, longevity and age related diseases

On April 18, 2007 an international meeting on Pathophysiology of Ageing, Longevity and Age-Related Diseases was held in Palermo, Italy. Several interesting topics on Cancer, Immunosenescence, Age-related inflammatory diseases and longevity were discussed. In this report we summarize the most important issues. However, ageing must be considered an unavoidable end point of the life history of each individual, nevertheless the increasing knowledge on ageing mechanisms, allows envisaging many different strategies to cope with, and delay it. So, a better understanding of pathophysiology of ageing and age-related disease is essential for giving everybody a reasonable chance for living a long and enjoyable final part of the life.     

Diverse effects of three furocoumarins on human lymphocyte proliferation

The biological effects of three furocoumarins on the proliferation of human normal peripheral blood lymphocytes have been investigated. Mitogen-stimulated human lymphocytes were assayed "in vitro" by measuring 3H-thymidine (3H-TdR) incorporation in the presence and in the absence of 15-30 microM 3-carbethoxypsoralen (3-CPs), trimethylangelicin (TMA) and psoralen (PSR) with and without UV-A irradiation (365 nm). The three furocoumarins differ in their ability to form mono- and bi-functional adducts with DNA pyrimidine bases and in producing reactive species of oxygen. At low furocoumarin doses and short times of UV-A irradiation (15-30 sec) used in the present study, 3-CPs did not affect 3H-TdR incorporation in PHA-stimulated human lymphocytes, TMA strongly inhibited 3H-TdR incorporation, while, unexpectedly, PSR increased 3H-TdR incorporation in the absence of irradiation, likely acting, under these experimental conditions, as a co-mitogen.