Biochemistry (Moscow) (v.78, #9)
Bacteria and phenoptosis by O. A. Koksharova (963-970).
Genetically programmed death of an organism, or phenoptosis, can be found not only in animals and plants, but also in bacteria. Taking into account intrapopulational relations identified in bacteria, it is easy to imagine the importance of phenoptosis in the regulation of a multicellular bacterial community in the real world of its existence. For example, autolysis of part of the population limits the spread of viral infection. Destruction of cells with damaged DNA contributes to the maintenance of low level of mutations. Phenoptosis can facilitate the exchange of genetic information in a bacterial population as a result of release of DNA from lysed cells. Bacteria use a special “language” to transmit signals in a population; it is used for coordinated regulation of gene expression. This special type of regulation of bacterial gene expression is usually active at high densities of bacteria populations, and it was named “quorum sensing” (QS). Different molecules can be used for signaling purposes. Phenoptosis, which is carried out by toxin-antitoxin systems, was found to depend on the density of the population; it requires a QS factor, which is called the extracellular death factor. The study of phenoptosis in bacteria is of great practical importance. The components that make up the systems ensuring the programmed cell death, including QS factor, may be used for the development of drugs that will activate mechanisms of phenoptosis and promote the destruction of pathogenic bacteria. Comparative genomic analysis revealed that the genes encoding several key enzymes involved in apoptosis of eukaryotes, such as paracaspases and metacaspases, apoptotic ATPases, proteins containing NACHT leucine-rich repeat, and proteases similar to mitochondrial HtrA-like protease, have homologs in bacteria. Proteomics techniques have allowed for the first time to identify the proteins formed during phenoptosis that participate in orderly liquidation of Streptomyces coelicolor and Escherichia coli cells. Among these proteins enzymes have been found that are involved in the degradation of cellular macromolecules, regulatory proteins, and stress-induced proteins. Future studies involving methods of biochemistry, genetics, genomics, proteomics, transcriptomics, and metabolomics should support a better understanding of the “mystery” of bacterial programmed cell death; this knowledge might be used to control bacterial populations.
Keywords: bacteria; phenoptosis; programmed cell death; cell population; QS; autoinducers; extracellular death factor; comparative genomics; proteomics
Arguments against non-programmed aging theories by T. C. Goldsmith (971-978).
Until recently, non-programmed theories of biological aging were popular because of the widespread perception that the evolution process could not support the development and retention of programmed aging in mammals. However, newer evolutionary mechanics theories including group selection, kin selection, and evolvability theory support mammal programmed aging, and multiple programmed aging theories have been published based on the new mechanics. Some proponents of non-programmed aging still contend that their non-programmed theories are superior despite the new mechanics concepts. However, as summarized here, programmed theories provide a vastly better fit to empirical evidence and do not suffer from multiple implausible assumptions that are required by non-programmed theories. This issue is important because programmed theories suggest very different mechanisms for the aging process and therefore different mechanisms behind highly age-related diseases and conditions such as cancer, heart disease, and stroke.
Perspectives of mitochondrial medicine by D. B. Zorov; N. K. Isaev; E. Y. Plotnikov; D. N. Silachev; L. D. Zorova; I. B. Pevzner; M. A. Morosanova; S. S. Jankauskas; S. D. Zorov; V. A. Babenko (979-990).
Mitochondrial medicine was established more than 50 years ago after discovery of the very first pathology caused by impaired mitochondria. Since then, more than 100 mitochondrial pathologies have been discovered. However, the number may be significantly higher if we interpret the term “mitochondrial medicine” more widely and include in these pathologies not only those determined by the genetic apparatus of the nucleus and mitochondria, but also acquired mitochondrial defects of non-genetic nature. Now the main problems of mitochondriology arise from methodology, this being due to studies of mitochondrial activities under different models and conditions that are far from the functioning of mitochondria in a cell, organ, or organism. Controversial behavior of mitochondria (“friends and foes”) to some extent might be explained by their bacterial origin with possible preservation of “egoistic” features peculiar to bacteria. Apparently, for normal mitochondrial functioning it is essential to maintain homeostasis of a number of mitochondrial elements such as mitochondrial DNA structure, membrane potential, and the system of mitochondrial quality control. Abrogation of these elements can cause a number of pathologies that have become subjects of mitochondrial medicine. Some approaches to therapy of mitochondrial pathologies are discussed.
Keywords: mitochondria; mitochondrial diseases; mitochondrial DNA; membrane potential; mitochondrial quality control; mitochondria-targeted antioxidants; bacteria; phenoptosis
Fatal “Triad”: Lipotoxicity, oxidative stress, and phenoptosis by A. V. Rzheshevsky (991-1000).
Negative factors, such as the “magnificent” five that includes alcoholism, smoking, unhealthy food, lack of movement, and negative emotions, accompany a person almost from birth and trigger powerful internal biochemical reactions leading to disastrous consequences. Those new deleterious reactions force the organism to mobilize all of its internal reserves to neutralize, at least temporarily, the destructive effects of these negative factors. As a result of this continuous struggle for survival, body parts degenerate, starting from connective tissue protein molecules to entire newly formed organs (such as adipose tissue). Today we can state with certainty that the reason for the majority of widespread pathologies causing premature aging and death, such as atherosclerosis and arterial hypertension, is exactly those external negative factors that a person voluntary introduces into their life. However, the margin of safety that Nature enclosed in the human body is really amazing, allowing light-minded and self-destructive people to live up to 60 years and longer. It is quite possible that the lifespan will increase up to 100 years and more if a person stops destroying themself with negative emotions and bad habits, including unhealthy food and overeating. This article examines possible interconnection between unhealthy overeating and the theory of programmed aging and phenoptosis.
Keywords: metabolic syndrome; insulin resistance; obesity; lipotoxicity; oxidative stress; phenoptosis; programmed aging
Phenoptosis as genetically determined aging influenced by signals from the environment by A. V. Khalyavkin (1001-1005).
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.
Keywords: aging plasticity; environmental influences; origin of aging; retarded senescence; self-maintenance; reversibility of senescence
Effect of mitochondria-targeted antioxidant SkQ1 on programmed cell death induced by viral proteins in tobacco plants by A. D. Solovieva; O. Yu. Frolova; A. G. Solovyev; S. Yu. Morozov; A. A. Zamyatnin Jr. (1006-1012).
Programmed cell death (PCD) is the main defense mechanism in plants to fight various pathogens including viruses. The best-studied example of virus-induced PCD in plants is Tobacco mosaic virus (TMV)-elicited hypersensitive response in tobacco plants containing the N resistance gene. It was previously reported that the animal mitochondrial protein Bcl-xL, which lacks a homolog in plants, effectively suppresses plant PCD induced by TMV p50 — the elicitor of hyper-sensitive response in Nicotiana tabacum carrying the N gene. Our studies show that the mitochondria-targeted antioxidant SkQ1 effectively suppresses p50-induced PCD in tobacco plants. On the other hand, SkQ1 did not affect Poa semilatent virus TGB3-induced endoplasmic reticulum stress, which is followed by PCD, in Nicotiana benthamiana epidermal cells. These data suggest that mitochondria-targeted antioxidant SkQ1 can be used to study molecular mechanisms of PCD suppression in plants.
Keywords: mitochondria-targeted compounds; reactive oxygen species; hypersensitive response; ER stress; unfolded protein response
Post-reproductive life span and demographic stability by J. J. Mitteldorf; C. Goodnight (1013-1022).
Recent field studies suggest that it is common in nature for animals to outlive their reproductive viability. Post-reproductive life span has been observed in a broad range of vertebrate and invertebrate species. But post-reproductive life span poses a paradox for traditional theories of life history evolution. The commonly cited explanation is the “grandmother hypothesis”, which applies only to higher, social mammals. We propose that post-reproductive life span evolves to stabilize predator-prey population dynamics, avoiding local extinctions. In the absence of senescence, juveniles would be the most susceptible age class. If juveniles are the first to disappear when predation pressure is high, this amplifies the population’s risk of extinction. A class of older, senescent individuals can help shield the juveniles from predation, stabilizing demographics and avoiding extinction. If, in addition, the life history is arranged so that the older individuals are no longer fertile, the stabilizing effect is further enhanced.
Keywords: menopause; aging; senescence; programmed aging; adaptive aging; evolution
Evidence for aging theories from the study of a hunter—gatherer people (Ache of Paraguay) by G. Libertini (1023-1032).
In the late seventies, a small tribal population of Paraguay, the Ache, living under natural conditions, was studied. Data from this population turn out to be useful for considerations about evolutionary hypotheses on the aging phenomenon. 1) Ache show an age-related increasing mortality, which strongly limits the mean duration of life, as observed in other studies on mammal and bird species. 2) According to current theories on aging, in the wild very few or no individual reach old age and, so, aging cannot be directly influenced by natural selection. However, data from our population show that a significant proportion of the population reaches in the wild 60 and 70 years of age. 3) Data from Ache are also in agreement with the observation about an inverse correlation between extrinsic mortality and deaths due to the age-related increasing mortality. 4) For many gerontologists, the age-related decline of vital functions is a consequence of the gradual decline of cell turnover, genetically determined and regulated by the declining duplication capacities of stem cells. The current interpretation is that these restrictions are a general defense against the proliferation of any tumoral mass. However, among wild Ache cancer is virtually unknown in non-elderly subjects, and only among older individuals are there deaths attributable to oncological diseases. Moreover, fitness decline begins long before oncological diseases have fatal effects in significant numbers. This completely disproves the current hypothesis, because a supposed defense against a deadly disease cannot exterminate a population before the disease begins to kill. These data are consistent with similar data from other species studied under natural conditions, and they bring new arguments against the non-adaptive interpretation of aging and in support of the adaptive interpretation.
Keywords: senescence; evolution; telomere; telomerase; cancer
Age fluctuations in mortality of mice with mutation causing growth retardation by A. G. Malygin (1033-1042).
Lifespan of mice over a number of consecutive generations of descendants of a male with a mutation causing growth retardation was studied. The mutant and normally developing (normal) mice were obtained by crossbreeding of mutant males with normal females from the same brood. The mutant females were infertile. Mortality of the mutant and normal mice was shown to fluctuate depending on age. The curve of dependence of lifespan on their serial number in a series of lifespan increase (mortality rank curve) had the form of evident steps for the mutant mice, while in normal mice this feature was less pronounced. These steps indicate that in the course of development of mice stages with low mortality are alternately replaced by stages with increased mortality. One month after birth, the first stage of stable development of mutant males and females is replaced by a stage with abnormally high mortality, which coincides with the period of their maximal backlog in weight compared to the normal animals. Within two months, surviving mutants catch up in weight with normally developing mice and externally become indistinguishable from them. The steps are reproduced on mortality rank curves in mutant and normal mice, both in groups of mice of different sexes and in parallel same-sex groups. The observed phenomenon is interpreted within the hypothesis of a genetic aging program in mice that provides periodic changes when stages of great viability are followed by stages of increased sensitivity to the external risk factors causing death. Less-expressed steps on mortality rank curves of normal females were shown to be enhanced by the removal from the sample of parous females and animals with tumors. Results of the study indicate the possibility of detecting in humans of ontogenesis-programmed stages of high and low sensitivity to external influences and the prospect of the development of effective measures to prevent risks of premature death.
Keywords: lifespan; mice; growth retardation; development stages; mortality intensity; Gompertz-Makeham equation
Advanced glycation of cellular proteins as a possible basic component of the “master biological clock” by F. F. Severin; B. A. Feniouk; V. P. Skulachev (1043-1047).
During the last decade, evidence has been accumulating supporting the hypothesis that aging is genetically programmed and, therefore, precisely timed. This hypothesis poses a question: what is the mechanism of the biological clock that controls aging? Measuring the level of the advanced glycation end products (AGE) is one of the possible principles underlying the functioning of the biological clock. Protein glycation is an irreversible, non-enzymatic, and relatively slow process. Moreover, many types of cells have receptors that can measure AGE level. We propose the existence of a protein that has a lifespan comparable to that of the whole organism. Interaction of the advanced glycation end product generated from this protein with a specific AGE receptor might initiate apoptosis in a vitally important non-regenerating tissue that produces a primary juvenile hormone. This could result in the age-dependent decrease in the level of this hormone leading to aging of the organism.
Keywords: biological clock; aging; protein glycation; melatonin; juvenile hormone; AGE; RAGE
How does the body know how old it is? Introducing the epigenetic clock hypothesis by J. J. Mitteldorf (1048-1053).
Animals and plants have biological clocks that help to regulate circadian cycles, seasonal rhythms, growth, development, and sexual maturity. It is reasonable to suspect that the timing of senescence is also influenced by one or more biological clocks. Evolutionary reasoning first articulated by G. Williams suggests that multiple, redundant clocks might influence organismal aging. Some aging clocks that have been proposed include the suprachiasmatic nucleus, the hypothalamus, involution of the thymus, and cellular senescence. Cellular senescence, mediated by telomere attrition, is in a class by itself, having recently been validated as a primary regulator of aging. Gene expression is known to change in characteristic ways with age, and in particular DNA methylation changes in age-related ways. Herein, I propose a new candidate for an aging clock, based on epigenetics and the state of chromosome methylation, particularly in stem cells. If validated, this mechanism would present a challenging target for medical intervention.
Keywords: biological clock; senescence; rhythm; maturation; aging; programmed aging; adaptive aging; methylation; epigenetics; gene expression
Telomere biology: Cancer firewall or aging clock? by J. J. Mitteldorf (1054-1060).
It has been a decade since the first surprising discovery that longer telomeres in humans are statistically associated with longer life expectancies. Since then, it has been firmly established that telomere shortening imposes an individual fitness cost in a number of mammalian species, including humans. But telomere shortening is easily avoided by application of telomerase, an enzyme which is coded into nearly every eukaryotic genome, but whose expression is suppressed most of the time. This raises the question how the sequestration of telomerase might have evolved. The predominant assumption is that in higher organisms, shortening telomeres provide a firewall against tumor growth. A more straightforward interpretation is that telomere attrition provides an aging clock, reliably programming lifespans. The latter hypothesis is routinely rejected by most biologists because the benefit of programmed lifespan applies only to the community, and in fact the individual pays a substantial fitness cost. There is a long-standing skepticism that the concept of fitness can be applied on a communal level, and of group selection in general. But the cancer hypothesis is problematic as well. Animal studies indicate that there is a net fitness cost in sequestration of telomerase, even when cancer risk is lowered. The hypothesis of protection against cancer has never been tested in animals that actually limit telomerase expression, but only in mice, whose lifespans are not telomerase-limited. And human medical evidence suggests a net aggravation of cancer risk from the sequestration of telomerase, because cells with short telomeres are at high risk of neoplastic transformation, and they also secrete cytokines that exacerbate inflammation globally. The aging clock hypothesis fits well with what is known about ancestral origins of telomerase sequestration, and the prejudices concerning group selection are without merit. If telomeres are an aging clock, then telomerase makes an attractive target for medical technologies that seek to expand the human life- and health-spans.
Keywords: telomere; telomerase; cancer; programmed aging; adaptive aging; evolution
Studies that shed new light on aging by H. L. Katcher (1061-1070).
I will first discuss how all aging models that assume that the aged cell has irreversibly lost its youthful capabilities through such mechanisms as accumulated dysfunction, accumulated damage, and/or accumulation of toxic byproducts of metabolism have been shown to be incorrect. I will then briefly discuss models of aging and propose an experiment that would distinguish between those models and provide a basis for organismic rejuvenation.
Keywords: aging; aging mechanisms; theories of aging; parabiosis; cross-age transplantation; rejuvenation; cellular aging; age-dependent transcriptional patterns