From Carrel to Hayflick and back, or what we got from the 100-year cytogerontological studies

The history of gerontological experiments on cell cultures is reviewed. Cytogerontological studies and aging theories by Weismann, Carrel, Hayflick, and the author are compared. It is emphasized that the basic notion of aging mechanisms was deeply revised several times within the 20th century. It is concluded that at present the aging of multicellular organisms cannot be satisfactorily explained with the help of cytogerontological studie’s data. Experiments on cell cultures need to be combined with fundamental gerontological studies, including survival curve analysis for humans or experimental animals.     

Mitochondrial regulation of cardiac aging

Aging is associated with progressive decline in cardiac structure and function. Accumulating evidence in model organisms and humans links cardiac aging to mitochondrial regulation, encompassing a complex interplay of mitochondrial morphology, mitochondrial ROS, mitochondrial DNA mutations, mitochondrial unfolded protein response, nicotinamide adenine dinucleotide levels and sirtuins, as well as mitophagy. This review summarizes the recent discoveries on the mitochondrial regulation of cardiac aging and the possible molecular mechanisms underlying the anti-aging effects, as well as the potential interventions that alleviate aging-related cardiac diseases and attenuate cardiac aging via the regulation of mitochondria.     

A therapeutic role for sirtuins in diseases of aging?

The sirtuins are a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Among the many genes that have been shown to affect aging in model organisms, sirtuin genes are unique in that their activity level is positively correlated with lifespan (i.e. they are anti-aging genes). Sirtuins are a druggable class of enzymes (i.e. amenable to intervention by small molecules) that could have beneficial effects on a variety of human diseases. In view of the many functions of Sirtuin 1 (SIRT1) in cells, this review focuses on its role in regulating important aspects of mitochondrial biology. Mitochondria have been linked to aging, and also to diseases of aging. Thus, sirtuins might provide a key link between mitochondrial dysfunction, aging and metabolic disease.     

Autophagy and aging

Genetic inhibition of autophagy induces degenerative changes in mammalian tissues that resemble those associated with aging, and normal and pathological aging are often associated with a reduced autophagic potential. Pharmacological or genetic manipulations that increase life span in model organisms often stimulate autophagy, and its inhibition compromises the longevity-promoting effects of caloric restriction, Sirtuin 1 activation, inhibition of insulin/insulin growth factor signaling, or the administration of rapamycin, resveratrol, or spermidine. Here, we discuss the probable cause and effect relationship between perturbed autophagy and aging, as well as possible molecular mechanisms that may mediate the anti-aging effects of autophagy.     

Does Aging Have a Purpose?

Ideas of proponents and opponents of programmed aging concerning the expediency of this phenomenon for the evolution of living organisms are briefly considered. We think that evolution has no “gerontological” purpose, because the obligate restriction of cell proliferation during the development of multicellular organisms is a factor that “automatically” triggers aging due to the accumulation of various macromolecular lesions in cells as a result of the suppression, or even complete cessation of emergence of new, intact cells. This leads to the “dilution” of stochastic damage (the most important of which is DNA damage) at the level of the entire cellular population. Some additional arguments in favor of the inexpediency of aging for both species and individuals are also listed.     

A longer and healthier life with TOR down-regulation: genetics and drugs

Genetic down-regulation of a major nutrient-sensing pathway, TOR (target of rapamycin) signalling, can improve health and extend lifespan in evolutionarily distant organisms such as yeast and mammals. Recently, it has been demonstrated that treatment with a pharmacological inhibitor of the TOR pathway, rapamycin, can replicate those findings and improve aging in a variety of model organisms. The proposed underlying anti-aging mechanisms are down-regulated translation, increased autophagy, altered metabolism and increased stress resistance.     

Which aging in yeast is “true”?

Two model systems, “replicative aging” and “chronological aging” (CA), which are used for gerontological research on the yeast Saccharomyces cerevisiae, are compared. In the first case, the number of daughter cells generated by an individual mother cell before cell propagation irreversibly stops is analyzed. This makes the model very similar to the well-known Hayflick model. In the case of CA, the survival of yeast cell population in the stationary phase of growth is studied. It is noted that the second model is similar to the “stationary phase aging” model, which is used in the author’s laboratory for cytogerontological studies on animal and human cells. It is assumed that the concept of cell proliferation restriction as the main cause of age-related accumulation in the cells of multicellular organisms of macromolecular defects (primarily DNA damage) leading to deterioration of tissue and organ functioning and, as a result, to an increase in the death probability allows explaining how the aging process proceeds in almost any living organisms. Apparently, in all cases, this process is initiated by the appearance of slow propagating (or not propagating at all) cells, which leads to the termination of “dilution,” with the help of new cells, of macromolecular defects accumulating at the level of whole cell population. It is concluded that data on the geropromoter or geroprotector activity of various factors obtained in tests on the yeast CA model can be used with a high reliability to understand the mechanisms of human aging and longevity.     

Slowing down aging from within: mechanistic aspects of anti-aging hormetic effects of mild heat stress on human cells

Since aging is primarily the result of a failure of maintenance and repair mechanisms, various approaches are being developed in order to stimulate these pathways and modulate the process of aging. One such approach, termed hormesis, involves challenging cells and organisms by mild stress that often results in anti-aging and life prolonging effects. In a series of experimental studies, we have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These beneficial effects of repeated challenge include the maintenance of stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses, and enhanced levels of cellular antioxidant ability. In order to elucidate the molecular mechanisms of hormetic effects of RMHS, we are now undertaking studies on signal transduction pathways, energy production and utilisation kinetics, and the proteomic analysis of patterns of proteins synthesised and their posttranslational modifications in various types of human cells undergoing cellular aging in vitro. Human applications of hormesis include early intervention and modulation of the aging process to prevent or delay the onset of age-related conditions, such as sarcopenia, Alzheimer's disease, Parkinson's disease, cataracts and osteoporosis.     

Interpretation of data about the impact of biologically active compounds on viability of cultured cells of various origin from a gerontological point of view

Problems related to the interpretation of data obtained during testing of potential geroprotectors in cytogerontological experiments are considered. It is emphasized that such compounds/physical factors should influence the processes leading to the age-related increase of death probability of multicellular organisms (primarily human, in whose aging gerontologists are mainly interested). However, in the authors’ opinion, compounds that can be used to treat age-related diseases can hardly be classified as geroprotectors. It is noted that, in the model systems using cultured cells, researchers usually evaluate their viability, the criteria of which strongly depend on the aging theory that is shared by the experimenters. In addition, it is very important what cells are used in the studies—normal or transformed cells of multicellular organisms, unicellular eukaryotic or prokaryotic organisms, etc. In particular, the biologically active compounds that decrease the viability of cultured cancer cells, similarly to the compounds that increase the viability of normal cultured cells, may increase the life span of experimental animals and humans. Various problems with interpretation of data obtained with the Hayflick model, the stationary phase aging model, and the cell kinetics model, as well as in experiments on evaluation of cell colony-forming efficiency, are analyzed. The approaches discussed are illustrated on the example of the results of gerontological studies of rapamycin, a well-known mTOR inhibitor. It is assumed that factors retarding the stationary phase aging (chronological aging) of cultured cells are, apparently, the most promising geroprotectors, although the specific mechanisms of their action may vary considerably.     

益生菌抗衰老作用机制研究进展

衰老会引起机体诸多不良的生理变化并增加对疾病的易感性,明确引发衰老的机制对于寻找其干预措施至关重要。研究发现,自由基氧化应激、炎症性衰老、免疫衰老、肠道菌群失调是引发衰老的相关机制。益生菌被报道具有潜在的延缓衰老作用,比较分析了常用益生菌抗衰老评价模型,并从衰老引发机制出发,重点综述了益生菌对肠道菌群的调节机制和抗衰老相关信号通路的影响,旨为进一步研究益生菌抗衰老作用提供新思路。     

Changes in the circadian biorhythms in animal and human ontogeny

It has been demonstrated that from the early stages of postnatal life up to adult age, gradual development of circadian amplitudes invariably takes place which may lead up to a complete absence of the diurnal rhythm in senile organisms. These changes are observed at various levels of organization of homeostatic systems (from cellular to organismic ones). A discussion is made of a possibility of evaluation of the level of adaptability and reliability of biological systems, as well as of their functional optimum via the analysis of circadian organization in ontogenesis, including gerontological problems (differentiation into age periods, biological age).     

Reproductive aging: insights from model organisms

Aging was once thought to be the result of a general deterioration of tissues as opposed to their being under regulatory control. However, investigations in a number of model organisms have illustrated that aspects of aging are controlled by genetic mechanisms and are potentially manipulable, suggesting the possibility of treatment for age-related disorders. Reproductive decline is one aspect of aging. In model organisms and humans of both sexes, increasing age is associated with both a decline in the number of progeny and an increased incidence of defects. The cellular mechanisms of reproductive aging are not well understood, although a number of factors, both intrinsic and extrinsic to an organism's germline, may contribute to aging phenotypes. Recent work in a variety of organisms suggests that nuclear organization and nuclear envelope proteins may play a role in these processes.     

The spatial association of gene expression evolves from synchrony to asynchrony and stochasticity with age

For multicellular organisms, different tissues coordinate to integrate physiological functions, although this systematically and gradually declines in the aging process. Therefore, an association exists between tissue coordination and aging, and investigating the evolution of tissue coordination with age is of interest. In the past decade, both common and heterogeneous aging processes among tissues were extensively investigated. The results on spatial association of gene changes that determine lifespan appear complex and paradoxical. To reconcile observed commonality and heterogeneity of gene changes among tissues and to address evolution feature of tissue coordination with age, we introduced a new analytical strategy to systematically analyze genome-wide spatio-temporal gene expression profiles. We first applied the approach to natural aging process in three species (Rat, Mouse and Drosophila) and then to anti-aging process in Mouse. The results demonstrated that temporal gene expression alteration in different tissues experiences a progressive association evolution from spatial synchrony to asynchrony and stochasticity with age. This implies that tissue coordination gradually declines with age. Male mice showed earlier spatial asynchrony in gene expression than females, suggesting that male animals are more prone to aging than females. The confirmed anti-aging interventions (resveratrol and caloric restriction) enhanced tissue coordination, indicating their underlying anti-aging mechanism on multiple tissue levels. Further, functional analysis suggested asynchronous DNA/protein damage accumulation as well as asynchronous repair, modification and degradation of DNA/protein in tissues possibly contributes to asynchronous and stochastic changes of tissue microenvironment. This increased risk for a variety of age-related diseases such as neurodegeneration and cancer that eventually accelerate organismal aging and death. Our study suggests a novel molecular event occurring in aging process of multicellular species that may represent an intrinsic molecular mechanism of aging.     

益生菌潜在的抗衰老作用

在机体衰老的过程中,会出现2种明显的生理变化即免疫功能衰退和氧化损伤,本文从益生菌的免疫调节作用和抗氧化作用两方面讨论了它们对衰老过程的影响,提出益生菌潜在的抗衰老作用与其抗氧化和免疫调节作用之间存在必然的联系。目前,在部分加速衰老模型中对益生菌抗衰老的研究结果令人鼓舞。本文分析了现在普遍采用的几种衰老评价模型的机制,并指出在筛选和评价益生菌的抗衰老作用时,有必要进一步建立和完善采用与衰老过程相关酶作为靶位酶的体外抗衰老模型,如单胺氧化酶抑制模型或可以反应氧化损伤的细胞模型如Caco-2细胞模型。在此基础上,应用特定的衰老动物模型对体外试验所获得的结果予以验证,以期更客观有效地评价益生菌发挥其抗衰老功效的作用机制。     

调节慢性炎症防治衰老相关疾病的研究进展

衰老是应激、损伤、感染、免疫反应衰退以及代谢障碍等综合作用积累的结果。细胞在衰老的过程中会分泌大量的炎性因子。相关研究表明,老年人的皮肤及粘膜对细菌、病毒感染、外伤等等方面的抵抗和防御能力明显低于青年人,炎性因子不断增多,加速细胞衰老。由此可见,控制慢性炎症可能是干预衰老的有效途径。生物活性透明质酸可能通过诱导防卫素分泌和与CD44/TLR4受体结合,抑制细菌生长和炎症进展,从而发挥抗衰老作用。本文对有关慢性炎症和衰老之间的关系的研究进行综述,探讨生物活性透明质酸对慢性炎症的调节作用及其抗衰老机制。     

Near-to-perfect homeostasis: examples of universal aging rule which germline evades

Aging is considered to be a progressive decline in an organism's functioning over time and is almost universal throughout the living world. Currently, many different aging mechanisms have been reported at all levels of biological organization, with a variety of biochemical, metabolic, and genetic pathways involved. Some of these mechanisms are common across species, and others work different, but each of them is constitutive. This review describes the common characteristics of the aging processes, which are consistent changes over time that involve either the accumulation or depletion of particular system components. These accumulations and depletions may result from imperfect homeostasis, which is the incomplete compensation of a particular biological process with another process evolved to compensate it. In accordance with disposable-soma theory, this imperfection in homeostasis may originate as a function of cell differentiation as early as in yeasts. It may result either from antagonistic pleiotropy mechanisms, or be simply negligible as a subject of natural selection if an adverse effect of the accumulation phenotypically manifests in organism's post-reproductive age. If this phenomenon holds true for many different functions it would lead to the occurrence of a wide variety of aging mechanisms, some of which are common among species, while others unique, because aging is the inherent property of most biological processes that have not yet evolved to be perfectly in balance. Examples of imperfect homeostasis mechanisms of aging, the ways in which germ line escapes from them, and the possibilities of anti-aging treatment are discussed in this review.     

An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations

Aging is an inherently complex process that is manifested within an organism at genetic, molecular, cellular, organ, and system levels. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of aging. The "oxidative stress theory" holds that a progressive and irreversible accumulation of oxidative damage caused by ROS impacts on critical aspects of the aging process and contributes to impaired physiological function, increased incidence of disease, and a reduction in life span. While compelling correlative data have been generated to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidatively mediated damage and aging has not been strongly established. The goal of this minireview is to broadly describe mechanisms of in vivo ROS generation, examine the potential impact of ROS and oxidative damage on cellular function, and evaluate how these responses change with aging in physiologically relevant situations. In addition, the mounting genetic evidence that links oxidative stress to aging is discussed, as well as the potential challenges and benefits associated with the development of anti-aging interventions and therapies.     

Anti-aging function and molecular mechanism of Radix Astragali and Radix Astragali preparata via network pharmacology and PI3K/Akt signaling pathway

BackgroundRadix Astragali (RA) consists of the dried root of Astragalus membranaceus Bunge and is one of the most frequently used dietetic Chinese herbs to treat inflammation and neurodegenerative disease among other conditions. Radix Astragali preparata (RAP) is a medicinal form of RA. RA and RAP have been used as anti-aging agent, however, the mechanisms underlying their effects are still unclear.PurposeConsidering the wide application of RA and RAP in clinical practice, it is necessary to identify the better product between the two and elucidate the molecular mechanism responsible for their anti-aging effects.Study DesignIn this study, network pharmacology integrated with molecular biology techniques were employed to explore the possible mechanism of RA and RAP against aging.MethodsAging animal models were constructed by exposure to D-galactose (D-gal), and the anti-aging effect of RA and RAP were determined based on behavior tests and histomorphological observation. Network pharmacology was performed to construct the “compound-target-pathway” network. Gene and protein expression of possible targets were validated and analyzed using qRT-PCR and Western blotting.ResultsTreatment by RA and RAP could alleviate the symptoms of aging such as a decrease in body weight and organ indices, behavioral impairment, increased oxidative stress, weaken histopathological evaluation. The effect of RAP was more pronounced than that of RA in preventing aging process in a mouse model. The anti-aging effect of RA and RAP is associated with the balance of oxidative stress and activation of PI3K/Akt signaling pathway.ConclusionUsing an integrated strategy of network pharmacology and molecular biology we attempted to elucidate the mechanisms of action of RA and RAP.