Biochemistry (Moscow) (v.77, #7)

What is “phenoptosis” and how to fight it? by V. P. Skulachev (689-706).
Phenoptosis is the death of an organism programmed by its genome. Numerous examples of phenoptosis are described in prokaryotes, unicellular eukaryotes, and all kingdoms of multicellular eukaryotes (animals, plants, and fungi). There are very demonstrative cases of acute phenoptosis when actuation of a specific biochemical or behavioral program results in immediate death. Rapid (taking days) senescence of semelparous plants is described as phenoptosis controlled by already known genes and mediated by toxic phytohormones like abscisic acid. In soya, the death signal is transmitted from beans to leaves via xylem, inducing leaf fall and death of the plant. Mutations in two genes of Arabidopsis thaliana, required for the flowering and subsequent formation of seeds, prevent senescence, strongly prolonging the lifespan of this small semelparous grass that becomes a big bush with woody stem, and initiate substitution of vegetative for sexual reproduction. The death of pacific salmon immediately after spawning is surely programmed. In this case, numerous typical traits of aging, including amyloid plaques in the brain, appear on the time scale of days. There are some indications that slow aging of higher animals and humans is also programmed, being the final step of ontogenesis. It is assumed that stepwise decline of many physiological functions during such aging increases pressure of natural selection on organisms stimulating in this way biological evolution. As a working hypothesis, the biochemical mechanism of slow aging is proposed. It is assumed that mitochondria-generated reactive oxygen species (ROS) is a tool to stimulate apoptosis, an effect decreasing with age the cell number (cellularity) of organs and tissues. A group of SkQ-type substances composed of plastoquinone and a penetrating cation were synthesized to target an antioxidant into mitochondria and to prevent the age-linked rise of the mitochondrial ROS level. Such targeting is due to the fact that mitochondria are the only cellular organelles that are negatively charged compared to the cytosol. SkQs are shown to strongly decrease concentration of ROS in mitochondria, prolong lifespan of fungi, invertebrates, fish, and mammals, and retard appearance of numerous traits of aging. Clinical trials of SkQ1 (plastoquinonyl decyltriphenylphosphonium) have been successfully completed so that the Ministry of Health of the Russian Federation recommends drops of very dilute (0.25 μM) solution of this antioxidant as a medicine to treat the syndrome of dry eye, which was previously considered an incurable disease developing with age. These drops are already available in drugstores. Thus, SkQ1 is the first mitochondria-targeted drug employed in medical practice.
Keywords: evolution; phenoptosis; programmed aging; mitochondria; antioxidants; therapy of dry eye syndrome

Classification of phenoptotic phenomena by G. Libertini (707-715).
Phenoptosis is defined as the programmed death of an organism. In a more detailed formulation of the concept, it is the death of an individual caused by its own actions or by actions of close relatives (and not by accidents or age-independent diseases), which is determined by genes that are favored by natural selection and in certain cases increase the evolvability of organisms. This category of phenomena cannot be justified in terms of individual selection and needs always a justification in terms of supra-individual selection. Four types of phenoptosis are proposed (A, obligatory and rapid; B, obligatory and slow; C, optional; D, indirect). Examples of each type and subtype are given. The classification is discussed in its meaning and implications, and compared with another classification of end life types largely based on the classical concept of senescence.
Keywords: phenoptosis; supra-individual selection; senescence; aging

Compelling evidence for an adaptive origin of aging has clashed with traditional evolutionary theory based on exclusively individual selection. The consensus view has been to try to understand aging in the context of a narrow, restrictive evolutionary paradigm, called the Modern Synthesis, or neo-Darwinism. But neo-Darwinism has shown itself to be inadequate in other ways, failing to account for stable ecosystems, for the evolution of sex and the maintenance of diversity and the architecture of the genome, which appears to be optimized for evolvability. Thus aging is not the only reason to consider overhauling the standard theoretical framework. Selection for stable ecosystems is rapid and efficient, and so it is the easiest modification of the neo-Darwinian paradigm to understand and to model. Aging may be understood in this context. More profound and more mysterious are the ways in which the process of evolution itself has been transformed in a boot-strapping process of selection for evolvability. Evolving organisms have learned to channel their variation in ways that are likely to enhance their long-term prospects. This is an expanded notion of fitness. Only in this context can the full spectrum of sophisticated adaptations be understood, including aging, sex, diversity, ecological interdependence, and the structure of the genome.
Keywords: evolvability; aging; sex; evolutionary capacitance; canalization

Pleiotropic theories for the evolutionary origins of senescence have been ascendant for forty years (see, for example, G. Williams (1957) Evolution, 11, 398–411; T. Kirkwood (1977) Nature, 270, 301–304), and it is not surprising that interpreters of demographic data seek to frame their results in this context. But some of that evidence finds a much more natural explanation in terms of adaptive aging. Here we re-interpret the 1997 results of the Centenarian Study in Boston, which found in their sample of centenarian women an excess of late childbearing. The finding was originally interpreted as a selection effect: a metabolic link between late menopause and longevity. But we demonstrate that this interpretation is statistically strained, and that the data in fact indicate a causal link: bearing a child late in life induces a metabolic response that promotes longevity. This conclusion directly contradicts some pleiotropic theories of aging that postulate a “cost of reproduction”, and it supports theories of aging as an adaptive genetic program.
Keywords: theories of aging; centenarians

The programmed vs. non-programmed aging controversy has now existed in some form for at least 150 years. For much of the XX century, it was almost universally believed that evolution theory prohibited programmed (adaptive) aging in mammals and there was little direct experimental or observational evidence favoring it. More recently, multiple new evolutionary mechanics concepts that support programmed aging and steadily increasing direct evidence favoring it overwhelmingly support the existence of programmed aging in humans and other organisms. This issue is important because the different theories suggest very different mechanisms for the aging process that in turn suggest very different paths toward treating and preventing age-related diseases.
Keywords: aging; senescence; evolution; gerontology

The theory of adaptive senescence, or phenoptosis (“altruistic suicide” of the organism), implies that mutations enhancing mortality growth with age (“senescence genes”) can be favored by selection under some circumstances, although the nature of these circumstances and the frequency of their occurrence are not clear. Here I demonstrate by means of computer simulation that senescence genes can spread in the population’s gene pool via the mechanism of kin selection if two conditions are met. First, the population must have high viscosity (low intermixing), which provides positive correlation between spatial proximity of individuals and their relatedness, an important precondition for kin selection. Second, prior to acquisition of the senescence genes, there must be a sufficiently fast decline in the reproductive potential with age, while viability should decrease slower or remain constant. These conditions are probably met in some territorial and social species with severe competition for social rank and mating partners.
Keywords: Hamilton’s rule; kin selection; phenoptosis; senescence; modeling

The phenoptosis problem: What is causing the death of an organism? Lessons from acute kidney injury by D. B. Zorov; E. Y. Plotnikov; S. S. Jankauskas; N. K. Isaev; D. N. Silachev; L. D. Zorova; I. B. Pevzner; N. V. Pulkova; S. D. Zorov; M. A. Morosanova (742-753).
Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems — the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism’s death.
Keywords: sudden death; multiple organ failure; apoptosis; kidney; mitochondria; antioxidant

One of the arguments against aging being programmed is the assumption that variation in the timing of aging-related outcomes is much higher compared to variation in timing of the events programmed by ontogenesis. The main objective of this study was to test the validity of this argument. To this aim, we compared absolute variability (standard deviation) and relative variability (coefficient of variation) for parameters that are known to be determined by the developmental program (age at sexual maturity) with variability of characteristics related to aging (ages at menopause and death). We used information on the ages at sexual maturation (menarche) and menopause from the nationally representative survey of the adult population of the United States (MIDUS) as well as published data for 14 countries. We found that coefficients of variation are in the range of 8–13% for age at menarche, 7–11% for age at menopause, and 16–21% for age at death. Thus, the relative variability for the age at death is only twice higher than for the age at menarche, while the relative variability for the age at menopause is almost the same as for the age at menarche.
Keywords: aging; variability; menarche; menopause; lifespan

Phenoptosis in yeasts by E. I. Sukhanova; A. G. Rogov; F. F. Severin; R. A. Zvyagilskaya (761-775).
The current view on phenoptosis and apoptosis as genetic programs aimed at eliminating potentially dangerous organisms and cells, respectively, is given. Special emphasis is placed on apoptosis (phenoptosis) in yeasts: intracellular defects and a plethora of external stimuli inducing apoptosis in yeasts; distinctive morphological and biochemical hallmarks accompanying apoptosis in yeasts; pro- and antiapoptotic factors involved in yeast apoptosis signaling; consecutive stages of apoptosis from external stimulus to the cell death; a prominent role of mitochondria and other organelles in yeast apoptosis; possible pathways for release of apoptotic factors from the intermembrane mitochondrial space into the cytosol are described. Using some concrete examples, the obvious physiological importance and expediency of altruistic death of yeast cells is shown. Poorly known aspects of yeast apoptosis and prospects for yeast apoptosis study are defined.
Keywords: yeasts; phenoptosis; apoptosis; mitochondria; endoplasmic reticulum; vacuole

Superoxide scavenging activity of plastoquinone derivative 10-(6′-plastoquinonyl)decyltriphenylphosphonium (SkQ1) by V. A. Chistyakov; E. V. Prazdnova; L. V. Gutnikova; M. A. Sazykina; I. S. Sazykin (776-778).
The plastoquinone derivative 10-(6′-plastoquinonyl)decyltriphenylphosphonium (SkQ1) has the ability to scavenge superoxide anion radical. This ability is manifested both in vitro and in vivo in experiments with the bacterium Escherichia coli. The protective effect of SkQ1 in vivo significantly exceeds that of ascorbic acid.
Keywords: Skulachev ions; SkQ1; superoxide anion radical; superoxide scavenging activity; E. coli

Cellularity loss and dilman’s problem: An in silico study by V. A. Chistyakov; Y. V. Denisenko (779-792).
We assume that prolonged trends of increasing concentration of hormones could be a consequence of deterioration of functioning of glands producing inhibitors of their synthesis. Such deterioration would result from loss of cellularity of the glands. Experiments in silico carried out using the model at show that, in principle, the diversity of hormonal effects that accompany phenoptosis of multicellular organisms can be provided with a simple “software mechanism”. This mechanism is based on the gradual loss of cellularity as a result of continuous run of apoptosis in some cells of the glands due to natural fluctuations in levels of intracellular inducers of apoptosis. The main practical sense of our work lies in the illustration of the fact that substances inhibiting cellularity loss can theoretically be effective suppressors of hormonal changes characteristic for aging.
Keywords: phenoptosis; apoptosis; aging; imitation modeling; cellularity loss; hormones; elevation theory

Longevity and mitochondrial membrane potential by D. A. Knorre; F. F. Severin (793-794).
In Saccharomyces cerevisiae yeast cells a decrease in the mitochondrial membrane potential caused by protonophores or by a loss of mitochondrial DNA leads to an increase in longevity (replicative life span). The loss of mitochondrial DNA also activates retrograde signaling that results in certain changes in transcription. Recently, Miceli and coauthors ((2011) Front. Genet., 2, 102) showed that retrograde response is triggered by a drop in the membrane potential. Independently, it has been shown that retrograde response activates autophagic mitochondrial degradation (mitophagy). Together, it suggests that activation of selective mitophagy increases lifespan by protecting cells from accumulation of damaged mitochondria in cells. Low concentrations of protonophores can be beneficial by increasing the accuracy of the mitophagosomal degradation of mitochondria with deleterious mutations in their DNA.
Keywords: yeast; mitochondria; mitophagy; retrograde signaling; aging

The classical approach of evolutionism is based on the concept of the survival of the fittest individuals. More and more data indicate that natural selection often acts with supra-individual mechanisms favoring genes and actions harmful for the individual. The most striking type of cases is when an individual kills himself or his offspring by actions genetically determined or favored. The neologism “phenoptosis” describes these events and implicates that they are not evolutionary anomalies but physiological phenomena determined by natural selection. The most important and familiar kind of phenoptosis, the “slow phenoptosis” or aging, which is currently considered an inevitable and scarcely changeable event, is transformed by this different interpretation into a function, in principle modifiable and manageable. Perhaps, the neologism “phenoptosis” will represent, together with the term supra-individual selection, the mark of a vital enrichment of evolutionism, conceived in broader terms of which the individual selection is just a particular case, and will be referred to as the brand and the standard for the start of a new era.
Keywords: phenoptosis; slow phenoptosis; apoptosis; aging; proapoptosis; supra-individual selection