Physiological scenarios of programmed loss of mitochondrial DNA function and death of yeast

Recently it was convincingly shown that the yeast Saccharomyces cerevisiae does possess the basic modules of programmed cell death machinery. As programmed cell death is suicide for a unicellular organism, it is reasonable to assume that they trigger the program when the death is beneficial for the rest of the population. Not surprisingly, most of the scenarios of physiological death of S. cerevisiae, i.e. cell death in stationary culture, during meiosis, during mating, and driven by viruses are dependent on quorum sensing, meaning that they depend on the cell density. Here we also discuss possible mechanisms that govern fitness decline during replicative aging of S. cerevisiae cells. We argue that loss of mitochondrial DNA function that occurs during replicative aging is programmed and adaptive. Indeed, yeast cells with nonfunctional mitochondrial DNA are known to be extremely stress-resistant, and also the presence of a subpopulation of such cells might protect the culture from degeneration by preventing the fixation of opportunistic mutations.     

Shorter life and reduced fecundity can increase colony fitness in virtual Caenorhabditis elegans

In the nematode Caenorhabditis elegans, loss of function of many genes leads to increases in lifespan, sometimes of a very large magnitude. Could this reflect the occurrence of programmed death that, like apoptosis of cells, promotes fitness? The notion that programmed death evolves as a mechanism to remove worn out, old individuals in order to increase food availability for kin is not supported by classic evolutionary theory for most species. However, it may apply in organisms with colonies of closely related individuals such as C. elegans in which largely clonal populations subsist on spatially limited food patches. Here, we ask whether food competition between nonreproductive adults and their clonal progeny could favor programmed death by using an in silico model of C. elegans. Colony fitness was estimated as yield of dauer larva propagules from a limited food patch. Simulations showed that not only shorter lifespan but also shorter reproductive span and reduced adult feeding rate can increase colony fitness, potentially by reducing futile food consumption. Early adult death was particularly beneficial when adult food consumption rate was high. These results imply that programmed, adaptive death could promote colony fitness in C. elegans through a consumer sacrifice mechanism. Thus, C. elegans lifespan may be limited not by aging in the usual sense but rather by apoptosis‐like programmed death.     

Cyclophilin D links programmed cell death and organismal aging in Podospora anserina

Cyclophilin D (CYPD) is a mitochondrial peptidyl prolyl‐cis,trans‐isomerase involved in opening of the mitochondrial permeability transition pore (mPTP). CYPD abundance increases during aging in mammalian tissues and in the aging model organism Podospora anserina. Here, we show that treatment of the P. anserina wild‐type with low concentrations of the cyclophilin inhibitor cyclosporin A (CSA) extends lifespan. Transgenic strains overexpressing PaCypD are characterized by reduced stress tolerance, suffer from pronounced mitochondrial dysfunction and are characterized by accelerated aging and induction of cell death. Treatment with CSA leads to correction of mitochondrial function and lifespan to that of the wild‐type. In contrast, PaCypD deletion strains are not affected by CSA within the investigated concentration range and show increased resistance against inducers of oxidative stress and cell death. Our data provide a mechanistic link between programmed cell death (PCD) and organismal aging and bear implications for the potential use of CSA to intervene into biologic aging.     

Aging in the colonial chordate,Botryllus schlosseri

What mechanisms underlie aging? One theory, the wear-and-tear model, attributes aging to progressive deterioration in the molecular and cellular machinery which eventually lead to death through the disruption of physiological homeostasis. The second suggests that life span is genetically programmed, and aging may be derived from intrinsic processes which enforce a non-random, terminal time interval for the survivability of the organism. We are studying an organism that demonstrates both properties: the colonial ascidian, Botryllus schlosseri. Botryllus is a member of the Tunicata, the sister group to the vertebrates, and has a number of life history traits which make it an excellent model for studies on aging. First, Botryllus has a colonial life history, and grows by a process of asexual reproduction during which entire bodies, including all somatic and germline lineages, regenerate every week, resulting in a colony of genetically identical individuals. Second, previous studies of lifespan in genetically distinct Botryllus lineages suggest that a direct, heritable basis underlying mortality exists that is unlinked to reproductive effort and other life history traits. Here we will review recent efforts to take advantage of the unique life history traits of B. schlosseri and develop it into a robust model for aging research.     

Ontogenetic peculiarities of regulation of apoptosis of hypothalamic neurosecretory cells in TNF-knockout mice

Tumor necrosis factor (TNF) participates in regulation of many processes, including carcinogenesis and apoptosis. However, at present, there are practically no studies on peculiarities of apoptosis control in tnf-knockout (tnf-/-) mice. These mice develop without morphologic abnormalities, but they seem to have impairment of many biological processes, such as inflammation, programmed cell death, etc. Therefore, the goal of our work was to study possible pathways of regulation of apoptosis in the absence of TNF in neurosecretory cells (NSC) of young and old mice. For this purpose, we determined immunohistochemically expression of apoptosis markers caspase-8, caspase-9, Bax, Bcl-2, Mcl-1, neuropeptide vasopressin and the apoptosis level in hypothalamus of tnf-knockout mice of different ages as compared with mice with unchanged level of TNF synthesis. It was shown that the apoptosis activation observed during aging did not depend on the tnf gene and that apoptosis at aging was caspase-dependent. It was revealed that at aging in mouse NSC the external cell death pathway with participation of caspase-8 is activated. The pathways mediating cell death in different neurosecretory centers at aging are different. Thus, in supraoptic nucleus (SON), in all studied animal groups, an important cause of the NSC apoptosis is Bax. In paraventricular nucleus (PVN), of the greater importance is a decrease of the anti-apoptotic protection. Hence, misbalance of synthesis of proteins of the Bcl-2 family plays an important role in development of senescent apoptosis.     

Identification of autophagy as a longevity-assurance mechanism in the aging model Podospora anserina

The filamentous ascomycete Podospora anserina is a well-established aging model in which a variety of different pathways, including those involved in the control of respiration, ROS generation and scavenging, DNA maintenance, proteostasis, mitochondrial dynamics, and programmed cell death have previously been demonstrated to affect aging and life span. Here we address a potential role of autophagy. We provide data demonstrating high basal autophagy levels even in strains cultivated under noninduced conditions. By monitoring an N-terminal fusion of EGFP to the fungal LC3 homolog PaATG8 over the lifetime of the fungus on medium with and without nitrogen supplementation, respectively, we identified a significant increase of GFP puncta in older and in nitrogen-starved cultures suggesting an induction of autophagy during aging. This conclusion is supported by the demonstration of an age-related and autophagy-dependent degradation of a PaSOD1-GFP reporter protein. The deletion of Paatg1, which leads to the lack of the PaATG1 serine/threonine kinase active in early stages of autophagy induction, impairs ascospore germination and development and shortens life span. Under nitrogen-depleted conditions, life span of the wild type is increased almost 4-fold. In contrast, this effect is annihilated in the Paatg1 deletion strain, suggesting that the ability to induce autophagy is beneficial for this fungus. Collectively, our data identify autophagy as a longevity-assurance mechanism in P. anserina and as another surveillance pathway in the complex network of pathways affecting aging and development. These findings provide perspectives for the elucidation of the mechanisms involved in the regulation of individual pathways and their interactions.     

Externally regulated programmed aging and effects of population stress on mammal lifespan

Programmed (adaptive) aging refers to the idea that mammals, including humans and other complex organisms, have evolved mechanisms that purposely cause or allow senescence or otherwise internally limit their lifespans in order to obtain an evolutionary advantage. Until recently, programmed aging had been thought to be theoretically impossible because of the mechanics of the evolution process. However, there is now substantial theoretical and empirical support for the existence of programmed aging in mammals. Therefore, a comprehensive approach to medical research on aging and age-related diseases must consider programmed aging mechanisms and the detailed nature of such mechanisms is of major importance. Theories of externally regulated programmed aging suggest that in mammals and other complex organisms, genetically specified senescence mechanisms detect local or temporary external conditions that affect the optimal lifespan for a species population and can adjust the lifespans of individual members in response. This article describes why lifespan regulation in response to external conditions adds to the evolutionary advantage produced by programmed aging and why a specific externally regulated programmed aging mechanism provides the best match to empirical evidence on mammal senescence.     

Quasi-programmed aging of budding yeast: a trade-off between programmed processes of cell proliferation,differentiation, stress response,survival and death defines yeast lifespan

Recent findings suggest that evolutionarily distant organisms share the key features of the aging process and exhibit similar mechanisms of its modulation by certain genetic, dietary and pharmacological interventions. The scope of this review is to analyze mechanisms that in the yeast Saccharomyces cerevisiae underlie: (1) the replicative and chronological modes of aging; (2) the convergence of these 2 modes of aging into a single aging process; (3) a programmed differentiation of aging cell communities in liquid media and on solid surfaces; and (4) longevity-defining responses of cells to some chemical compounds released to an ecosystem by other organisms populating it. Based on such analysis, we conclude that all these mechanisms are programs for upholding the long-term survival of the entire yeast population inhabiting an ecological niche; however, none of these mechanisms is a ?program of aging? - i.e., a program for progressing through consecutive steps of the aging process.     

Evolution of aging theories: Why modern programmed aging concepts are transforming medical research

Programmed aging refers to the idea that senescence in humans and other organisms is purposely caused by evolved biological mechanisms to obtain an evolutionary advantage. Until recently, programmed aging was considered theoretically impossible because of the mechanics of the evolution process, and medical research was based on the idea that aging was not programmed. Theorists struggled for more than a century in efforts to develop non-programmed theories that fit observations, without obtaining a consensus supporting any non-programmed theory. Empirical evidence of programmed lifespan limitations continued to accumulate. More recently, developments, especially in our understanding of biological inheritance, have exposed major issues and complexities regarding the process of evolution, some of which explicitly enable programmed aging of mammals. Consequently, science-based opposition to programmed aging has dramatically declined. This progression has major implications for medical research, because the theories suggest that very different biological mechanisms are ultimately responsible for highly age-related diseases that now represent most research efforts and health costs. Most particularly, programmed theories suggest that aging per se is a treatable condition and suggest a second path toward treating and preventing age-related diseases that can be exploited in addition to the traditional disease-specific approaches. The theories also make predictions regarding the nature of biological aging mechanisms and therefore suggest research directions. This article discusses developments of evolutionary mechanics, the consequent programmed aging theories, and logical inferences concerning biological aging mechanisms. It concludes that major medical research organizations cannot afford to ignore programmed aging concepts in assigning research resources and directions.     

Matricide in <Emphasis Type="Italic">Caenorhabditis elegans</Emphasis> as an example of programmed death of an animal organism: The role of mitochondrial oxidative stress

Nematode Caenorhabditis elegans is a widely used model for studying genetic and molecular mechanisms of lifespan regulation. The choice between two life strategies—normal aging and matricide (programmed death)-made by an adult hermaphroditic C. elegans organism is based on food availability and is also affected by different kinds of stress. We have tested a hypothesis concerning an increase in matricide probability as a result of oxidative stress; this hypothesis is based on the phenoptosis theory. High concentrations of paraquat, a strong mitochondrial stressor, were shown to increase matricide propensity. Mutants with a decreased antioxidant potential of mitochondria (nnt) were more sensitive to the reagent. On the other hand, paraquat concentrations required for this effect to be observed are toxic for the progeny, whereas at low paraquat concentration matricide frequency is the same in wild-type worms and nnt mutants. Therefore, one can assume that the molecular mechanisms of matricide initiation under normal conditions are not necessarily connected to mitochondrial oxidative stress.     

Cyclic nucleotide-gated channels are involved in phototransduction of dermal photoreceptors in Lymnaea stagnalis

Dermal photoreceptors in the pond snail Lymnaea stagnalis mediate the whole-body withdrawal response, including pneumostome closure, elicited by a shadow passing over the pneumostome area. The pneumostome closure response is part of the defense reaction in Lymnaea. The shadow or ‘light-off’ stimulus elicits activity in a higher order interneuron, RPeD11, which has a major role in mediating defensive withdrawal behavior elicited by noxious or threatening stimuli. Here, we tested our hypothesis that cyclic nucleotide-gated (CNG) channels are involved in the dermal photoreceptor-mediated transduction of the shadow stimulus. The response to the shadow stimulus recorded in RPeD11 was abolished by 500 μM cis-diltiazem, which blocks cGMP-activated conductance of CNG channels. On the other hand, the shadow response elicited in RPeD11 was not blocked by 2-amino ethyldiphenyl borate (2-APB), a transient receptor potential (TRP) channel blocker. Consistent with the electrophysiologic data, cis-diltiazem blocked the shadow-evoked withdrawal response, whereas 2-APB did not block the withdrawal response evoked by the shadow stimulus in intact freely behaving Lymnaea. Together, these findings support the hypothesis that the second messenger in dermal photoreceptors involves CNG and not TRP channels.     

The dual role of a yeast metacaspase: What doesn't kill you makes you stronger

Recent reports suggest that the yeast Saccharomyces cerevisiae caspase‐related metacaspase, Mca1, is required for cell‐autonomous cytoprotective functions that slow cellular aging. Because the Mca1 protease has previously been suggested to be responsible for programmed cell death (PCD) upon stress and aging, these reports raise the question of how the opposing roles of Mca1 as a protector and executioner are regulated. One reconciling perspective could be that executioner activation may be restricted to situations where the death of part of the population would be beneficial, for example during colony growth or adaptation into specialized survival forms. Another possibility is that metacaspases primarily harbor beneficial functions and that the increased survival observed upon metacaspase removal is due to compensatory responses. Herein, we summarize data on the role of Mca1 in cell death and survival and approach the question of how a metacaspase involved in protein quality control may act as killer protein.     

Phenoptosis as genetically determined aging influenced by signals from the environment

Aging is a complex and not well understood process. Two opposite concepts try to explain its causes and mechanisms — programmed aging and aging of “wear and tear” (stochastic aging). To date, much evidence has been obtained that contradicts the theories of aging as being due to accumulation of various damages. For example, creation of adequate conditions for the functioning of the organism’s components (appropriate microenvironment, humoral background, etc.) has been shown to cause partial or complete reversibility of signs of its aging. Programmed aging and death of an organism can be termed phenoptosis by analogy to the term apoptosis for programmed cell death (this term was first suggested by V. P. Skulachev). The necessity of this phenomenon, since A. Weismann, has been justified by the need for population renewal according to ecological and evolutionary requirements. Species-specific lifespan, age-dependent changes in expression pattern of genes, etc. are compatible with the concept of phenoptosis. However, the intraspecific rate of aging was shown to vary over of a wide range depending on living conditions. This means that the “aging program” is not set rigidly; it sensitively adjusts an individual to the specific realities of its habitat. Moreover, there are indications that in rather severe conditions of natural habitat the aging program can be completely cancelled, as the need for it disappears because of the raised mortality from external causes (high extrinsic mortality), providing fast turnover of the population.     

Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown

Background  

A family of aspartate-specific cysteinyl proteases, named caspases, mediates programmed cell death, apoptosis. In this function, caspases are important for physiological processes such as development and maintenance of organ homeostasis. Caspases are, however, also engaged in aging and disease development. The factors inducing age-related caspase activation are not known. Xanthurenic acid, a product of tryptophan degradation, is present in blood and urine, and accumulates in organs with aging.     

Molecular genetics of cell death in the nematode Caenorhabditis elegans

In C. elegans, cell death can be readily studied at the cellular, genetic, and molecular levels. Two types of death have been characterized in this nematode: (1) programmed cell death, which occurs as a normal component in development; and (2) pathological cell death which occurs aberrantly as a consequence of mutation. Analysis of mutations that disrupt programmed cell death in various ways has defined a genetic pathway for programmed cell death which includes genes that perform such functions as the determination of which cells die, the execution of cell death, the engulfment of cell corpses, and the digestion of DNA from dead cells. Molecular analysis is providing insightinto the nature of the molecules that function in these aspects of programmed cell death. Characterization of some genes that mutate to induce abnormal cell death has defined a novel gene family called degenerins that encode putative membrane proteins. Dominant alleles of at least two degenerin genes, mec-4 and deg-1, can cause cellular swelling and late onset neurodegeneration of specific groups of cells. © 1992 John Wiley & Sons, Inc.     

Essential mesenchymal role of small GTPase Rac1 in interdigital programmed cell death during limb development

Developing vertebrate limbs are often utilized as a model for studying pattern formation and morphogenetic cell death. Herein, we report that conditional deletion of Rac1, a member of the Rho family of proteins, in mouse limb bud mesenchyme led to skeletal deformities in the autopod and soft tissue syndactyly, with the latter caused by a complete absence of interdigital programmed cell death. Furthermore, the lack of interdigital programmed cell death and associated syndactyly was related to down-regulated gene expression of Bmp2, Bmp7, Msx1, and Msx2, which are known to promote apoptosis in the interdigital mesenchyme. Our findings from Rac1 conditional mutants indicate crucial roles for Rac1 in limb bud morphogenesis, especially interdigital programmed cell death.     

High plasma concentrations of acyl-coenzyme A binding protein (ACBP) predispose to cardiovascular disease: Evidence for a phylogenetically conserved proaging function of ACBP

Autophagy defects accelerate aging, while stimulation of autophagy decelerates aging. Acyl-coenzyme A binding protein (ACBP), which is encoded by a diazepam-binding inhibitor (DBI), acts as an extracellular feedback regulator of autophagy. As shown here, knockout of the gene coding for the yeast orthologue of ACBP/DBI (ACB1) improves chronological aging, and this effect is reversed by knockout of essential autophagy genes (ATG5, ATG7) but less so by knockout of an essential mitophagy gene (ATG32). In humans, ACBP/DBI levels independently correlate with body mass index (BMI) as well as with chronological age. In still-healthy individuals, we find that high ACBP/DBI levels correlate with future cardiovascular events (such as heart surgery, myocardial infarction, and stroke), an association that is independent of BMI and chronological age, suggesting that ACBP/DBI is indeed a biomarker of “biological” aging. Concurringly, ACBP/DBI plasma concentrations correlate with established cardiovascular risk factors (fasting glucose levels, systolic blood pressure, total free cholesterol, triglycerides), but are inversely correlated with atheroprotective high-density lipoprotein (HDL). In mice, neutralization of ACBP/DBI through a monoclonal antibody attenuates anthracycline-induced cardiotoxicity, which is a model of accelerated heart aging. In conclusion, plasma elevation of ACBP/DBI constitutes a novel biomarker of chronological aging and facets of biological aging with a prognostic value in cardiovascular disease.     

The shadow response of the cockroach periplaneta americana

We show that the “escape response” (running) of the cockroach Periplaneta americana is interrupted when the insect runs through a shadow. Shadows were cast by holding an opaque plastic sheet so that the cockroach ran beneath it. In control experiments, a similarly positioned clear plastic sheet was ineffective. Removal of the shadow stimulus allowed running to continue. The likelihood that cockroaches would resume running after removal of the shadow stimulus decreased with the time they were allowed to remain in shadow.