The variability of the mitochondrial genome in human aging: a key for life and death?

The impressive performance of the research in mitochondrial genetics and human aging in the last decade outlines a new scenery in which the inherited variation of the mitochondrial genome (mtDNA) may play a role in rate and quality of aging. This variation in humans was initially looked at as nearly neutral, and useful just for the reconstruction of human population history. However, recent data suggest that different mtDNA molecules are qualitatively different from each other. The aim of this paper is to discuss current ideas on the relationships among mitochondrial function, mtDNA inherited variation, and aging. The main processes where the mitochondrion is involved and the importance these processes have on aging and death of individuals will be described. A possible connection between programmed death phenomena (mitoptosis, apoptosis, phenoptosis) and rate and quality of aging will be discussed. Finally, the possible role played in these processes by the mtDNA germline variation will be explored.     

Human genome diversity: what about the other human genome project?

Although the Human Genome Project has been successful, the Human Genome Diversity Project, proposed in 1991, has so far failed to thrive. One of the main values in studying the human genome, however, will come from examining its variations and their effects. To do that in a systematic way, an active Human Genome Diversity Project, or something very similar, will ultimately prove vital. Such an effort will confront difficult ethical and political issues; this article reviews those issues and tries to show how they might be overcome.     

Do we have a right to an unmanipulated genome? The human genome as the common heritage of mankind

The human genome is commonly regarded as a ‘natural’ connection between all human beings, as it has been handed down to us by our predecessors. As such, it is believed to represent common heritage of humanity, e.g. a resource of outstanding value that should be the object of special protection and international concern. Some critics argue that germline manipulation would disrupt this natural heritage and that we have a duty to preserve the integrity of the human germline. However, a closer look reveals that the concept of common heritage of humanity does not necessarily imply the impermissibility of germline manipulation. If it is restricted to the prevention of severe diseases, germline manipulation does not represent a threat to the unity and identity of the human species, even though this would create a new form of relationship between human beings, namely that between a designer and a genetically designed person.     

Immobility: the key to family harmony?

The lethal fighting of larvae in many parasitoid species is a striking example of sibling rivalry. Theory has suggested that such fighting, and subsequent solitary development, might be irreversible, but phylogenetic evidence suggests otherwise. New empirical work now shows that the loss of mobility in parasitoid larvae, with the retention of fighting behaviour, is one way to escape the trap of solitary development.     

Founder virus population related to route of virus transmission: a determinant of intrahost human immunodeficiency virus type 1 evolution?

We and others have shown that in individual human immunodeficiency virus type 1 (HIV-1) infection, the adaptive evolution of HIV-1 is influenced by host immune competence. In this study, we tested the hypothesis that in addition to selective forces operating within the host, transmission bottlenecks have an impact on HIV-1 intrahost evolution. Therefore, we studied the intrahost evolution of the V3 region of the external glycoprotein gp120 of HIV-1 during the 3- and 5-year periods following seroconversion after parenteral versus sexual (male-to-male) transmission in 41 participants of the Amsterdam prospective cohorts of homosexual men (n = 31) and intravenous drug users (IVDUs; n = 10) who were AIDS free and had comparable numbers of CD4+ cells. We observed that HIV-1 strains in homosexual men accumulated over 5 years more nonsynonymous substitutions within the V3 loop than HIV-1 strains in IVDUs as a result of lower rates of nonsynonymous evolution in both the initial 3-year period from seroconversion and the following 2-year period as well as a larger proportion of nonsynonymous back substitutions in IVDUs. The mean numbers of synonymous substitutions did not differ between the two risk groups. Since HIV-1 strains in IVDUs could be distinguished from the viruses of homosexual men based on several nucleotide substitutions of which the most conserved is a synonymous substitution at the tip of the V3 loop (GGC pattern), we studied whether the founder virus population itself has an impact on the intrahost evolution of HIV-1. The mean number of nonsynonymous substitutions accumulated over 5 years within the V3 loop was lower in 10 IVDUs infected by the HIV-1 strains with the GGC signature than in 4 IVDUs infected by HIV-1 strains lacking this pattern, while the mean numbers of synonymous substitutions were similar in the two groups.     

Modulation of the immunological synapse: a key to HIV-1 pathogenesis?

AIDS is the result of a constant struggle between the lentivirus HIV and the immune system. Infection with HIV interferes directly with the function of CD4(+) T cells and manipulates the host immune response to the virus. Recent studies indicate that the viral protein Nef, a central player in HIV pathogenesis, impairs the ability of infected lymphocytes to form immunological synapses with antigen-presenting cells and affects T-cell-receptor-mediated stimulation. An integrative picture of the abnormal behaviour of HIV-infected lymphocytes is therefore emerging. We propose that modulating lymphocyte signalling, apoptosis and intracellular trafficking ensures efficient spread of the virus in the hostile environment of the immune system.     

Transients: the key to long-term ecological understanding?

Ecological theory has been dominated by a focus on long-term or asymptotic behavior as a way to understand natural systems. Yet experiments are done on much shorter timescales, and the relevant timescales for ecological systems can also be relatively short. Thus, there is a mismatch between the timescales of most experiments and the timescales of many theoretical investigations. However, recent work has emphasized the importance of transient dynamics rather than long-term behavior in ecological systems, enabling the examination of forces that allow coexistence on ecological timescales. Through an examination of what leads to transients in ecological systems, a deeper appreciation of the forces leading to persistence or coexistence in ecological systems emerges, as well as a general understanding of how population levels can change through time.     

The agmatine-degrading enzyme agmatinase: a key to agmatine signaling in rat and human brain?

Agmatinase, an ureohydrolase belonging to the arginase family, is widely expressed in mammalian tissues including the brain. Here, it may serve two different functions, the inactivation of the arginine derivative agmatine, a putative neurotransmitter, and the formation of the diamine putrescine. In order to identify the cellular sources of agmatinase expression in the brain, we generated a polyclonal monospecific antibody against recombinant rat agmatinase. With immunocytochemistry, selected areas of rat and human brain were screened. Clearly, in both species agmatinase-like immunoreactivity was predominantly detected in distinct populations of neurons, especially cortical interneurons. Also, principal neurons in limbic regions like the habenula and in the cerebellum robustly expressed agmatinase protein. When comparing the overall agmatinase expression with immunocytochemical data available for agmatine and polyamine biosynthetic enzymes, the observed pattern may argue in favor of an agmatine inactivating function rather than fueling the alternative pathway of polyamine synthesis. The putative neurotransmitter agmatine is seemingly involved with mental disorders. Therefore, agmatinase may be similarly important for pathogenesis. The normal expression profile of the protein as described here may therefore be altered under pathological conditions.     

Local lateral inhibition: a key to spike synchronization?

 Starting from the idea that neural group activity as such is unlikely to be immediately relevant for neural synchronization, we investigate mechanisms that act at the level of individual nerve impulses (spikes). Hence, we consider populations of formal spike-emitting ‘leaky integrate and fire’ neurons instead of networks built from non-spiking oscillators. After outlining the principle of synchronization for basic forms of recurrent impulse coupling by using a pair of simplified formal neurons, we show that local lateral inhibition results in robust impulse synchronization in networks with non-vanishing transmission delays. Received: 12 January 1994/Accepted in revised form: 25 April 1995