Biogerontology Research Papers - Academia.edu (original) (raw)

While the search for the “fountain of youth” has long been considered merely a fantasy, advances in regenerative medicine and biogerontology in the twenty-first century suggest that “the aspiration to modify the biological processes of... more

While the search for the “fountain of youth” has long been considered merely a fantasy, advances in regenerative
medicine and biogerontology in the twenty-first century
suggest that “the aspiration to modify the biological
processes of aging in humans—and thus delay the onset
of all age-related disadvantages, as well as compress
morbidity and mortality—may actually be achievable”.

The life span alteration after γ-irradiation and/or paraquat treatment in Drosophila in wild type strain Canton-S and strains with mutations of heat shock factor (1–4 alleles) and heat shock proteins (Hsp70Ba 304 , Hsp83 e6A , Hsp22... more

The life span alteration after γ-irradiation and/or paraquat treatment in Drosophila in wild type strain Canton-S and strains with mutations of heat shock factor (1–4 alleles) and heat shock proteins (Hsp70Ba 304 , Hsp83 e6A , Hsp22 EY09909 , Hsp67Bb EY099099 ) was investigated. Chronic low-dose rate γ-irradiation (0.017 and 0.17 cGy/h) on pre-imago stages was used as a priming dose (absorbed doses were 4 and 40 cGy). Paraquat, a free radical inducing agent, was a challenging factor (20 mM for 1 day). It was shown that chronic irradiation led to adaptive response in both sexes except homozygous males and females with mutations of Hsf 4 and Hsp70Ba 304 . The gender-specific differences in stress response were discovered in wild type strain Canton-S, Hsp22 EY09909 Hsp67Bb EY09909 homozygotes and Hsp83 e6A heterozygotes: the adaptive response persisted in males, but not in females. Thus, Drosophila Hsp and Hsf mutation homozygotes did not demonstrate the adaptive response in the majority of cases, implying an important role of those genes in radiation hormesis and adaptation to stresses.

Aging is currently stimulating intense interest of both researchers and the general public. In developed countries, the average life expectancy has increased by roughly 30 years within the last century, and human senescence has been... more

Aging is currently stimulating intense interest of both researchers and the general public. In developed countries, the average life expectancy has increased by roughly 30 years within the last century, and human senescence has been delayed by around a decade. Although aging is arguably the most familiar aspect of human biology, its proximate and ultimate causes have not been elucidated fully and understood yet. Nowadays there are two main approaches to the ultimate causes of aging. These are deterministic and stochastic models. The proximate theories constitute a distinct group of explanations. They focus on mechanistic causes of aging. In this view, there is no reason to believe that there is only one biological mechanism responsible for aging. The aging process is highly complex and results from an accumulation of random molecular damage. Currently, the disposable soma theory (DST), proposed by Thomas Kirkwood, is the most influential and coherent line of reasoning in biogerontology. This model does not postulate any particular mechanism underpinning somatic defense. Therefore, it is compatible with various models, including mechanistic and evolutionary explanations. Recently, however, an interesting theory of hyperfunction of mTOR as a more direct cause of aging has been formulated by Mikhail Blagosklonny, offering an entirely different approach to numerous problems and paradoxes in current biogerontology. In this view, aging is quasi-programmed, which means that it is an aimless continuation of developmental growth. This mTOR-centric model allows the prediction of completely new relationships. The aim of this article is to present and compare the views of both parties in the dispute, based on the results of some recent experimental studies, and the contemporary knowledge of selected major aspects of human aging and longevity.

Neurodegenerative diseases are often considered incurable with no efficient therapies to modify or halt the progress of disease, and ultimately lead to reduced quality of life and to death. Our knowledge of the nervous system in health... more

Neurodegenerative diseases are often considered incurable with no efficient therapies to modify or halt the progress of disease, and ultimately lead to reduced quality of life and to death. Our knowledge of the nervous system in health and disease has, however, increased considerably during the last fifty years and today, neuroscience reveals promising new strategies to deal with disorders of the nervous system. Some of these results have been implemented with success in the treatment of Parkinson's disease, a common neurodegenerative illness affecting approximately 1% of the population aged seventy or more. Parkinson's disease is characterized by a massive loss of dopaminergic neurons in the substantia nigra, leading to severe functional disturbance of the neuronal circuitry in the basal ganglia. A thorough description of basal ganglia circuitry in health and disease is presented. We describe how the functional disturbances seen in Parkinson's disease may be corrected a...

While the search for the “fountain of youth” has long been considered merely a fantasy, advances in regenerative medicine and biogerontology in the twenty-first century suggest that “the aspiration to modify the biological processes of... more

While the search for the “fountain of youth” has long been considered merely a fantasy, advances in regenerative medicine and biogerontology in the twenty-first century suggest that “the aspiration to modify the biological processes of aging in humans—and thus delay the onset of all age-related disadvantages, as well as compress morbidity and mortality—may actually be achievable”.

Evolutionary theory leads to the general expectation that dietary restriction will often result in increased survival probabilities, and thus increased lifespan. The reaction norm is a basic tool of evolutionary analysis that quantifies... more

Evolutionary theory leads to the general expectation that dietary restriction will often result in increased survival probabilities, and thus increased lifespan. The reaction norm is a basic tool of evolutionary analysis that quantifies the relationship between environmental parameters and functional characters, including reproduction and longevity. In rodents, the reaction norm connecting adult longevity to caloric intake is fairly steep; small changes in intake lead to large changes in longevity. If this strong quantitative relationship were evolutionarily conserved among all mammals, then the prospects for a substantial increase in human lifespan from caloric restriction would be very good. In theory, however, reaction norms are expected to evolve for fitness related characters such as reproduction and survival. It has been shown experimentally in Drosophila that dietary reaction norms readily evolve in the laboratory, suggesting that they can do so among mammals as well, particularly over the millions of years since contemporary rodents and primates last shared a common ancestor. Our previous work crudely estimates that the dietary reaction norms of rodents and humans have diverged substantially, with a very flat dietary reaction norm for human longevity. These general principles and our specific results suggest that the benefits from human caloric restriction would be minor.

Going back to the Ancient Greeks (e.g. Plato and Aristotle), philosophers have long asked profound questions such as “What is knowledge?” and “What is the good life?”. Such questions compel us to engage in a deeper level of introspection... more

Going back to the Ancient Greeks (e.g. Plato and Aristotle), philosophers have long asked profound questions such as “What is knowledge?” and “What is the good life?”. Such questions compel us to engage in a deeper level of introspection and examination than most of us are typically accustomed to in our daily lives. The philosophical question contemplated in this chapter is: “What constitutes ‘“well-ordered science’”?” Invoking a virtue epistemological construal of knowledge as “success from ability”, I argue that the study of pathology must be supplemented by the study of the determinates of exemplary positive phenotypes (e.g. healthy aging and happiness). This requires transcending the limitations of what I call “negative biology”, and treating “positive biology” as an integral element of well-ordered science in the 21st century. Positive biology can help bring to the fore the importance of understanding the evolutionary and life history of our species, thus helping to provide the intellectual frameworks needed to inspire the development of novel and feasible interventions to improve human health and happiness.

Degenerative diseases like cancer, Alzheimers, arthritis, cardiovascular disease and others have plagued the lives of millions upon millions of humans. General aging is connected to the pathogenesis of these diseases and also harms the... more

Degenerative diseases like cancer, Alzheimers, arthritis, cardiovascular disease and others have plagued the lives of millions upon millions of humans. General aging is connected to the pathogenesis of these diseases and also harms the health and living quality of humans by impairing the proper functioning of the body. Luckily, the degenerative processes that create degenerative disease and accelerate aging can be substantially modified by nutritional means. Diet can play a central role in determining the rate at which a body accumulates health-impairing damage but this paper will focus on the minimizing effect of nutritional supplements on degenerative processes. Research has indicated that addressing two core degenerative processes, oxidation and glycation, through the use of nutritional supplements, can minimize biological damage that leads to degenerative disorders. If protective supplements are effective and measurably reduce the wear and tear of degrading processes, then greater quality of life, biological function, and bodily health will take place in humans at more advanced chronological ages.

Background: Long-lived strains of dwarf mice carry mutations that suppress growth hormone (GH) and insulin-like growth factor I (IGF-I) signaling. The downstream effects of these endocrine abnormalities, however, are not well understood... more

Cutaneous wound healing is a complex process encompassing a number of overlapping events including leukocyte recruitment, matrix deposition, epithelialization, and ultimately resolution of inflammation with the formation of a mature scar.... more

Cutaneous wound healing is a complex process encompassing a number of overlapping events including leukocyte recruitment, matrix deposition, epithelialization, and ultimately resolution of inflammation with the formation of a mature scar. Morbidity associated with age-related delayed wound healing imposes an enormous social and financial burden; unless improved wound care strategies are developed the projected relative and absolute increase in the elderly population will further exacerbate this problem. In recent years insight has been gained into the impact of ageing on cellular and tissue responses, resulting from impaired cytokine signal transduction, unchecked inflammation, an altered balance of protein synthesis and degradation, and subsequent downstream effects on the rate and quality of the wound healing response. Further understanding of the complex interaction between the ageing cell and its microenvironment is essential in order to develop focussed therapeutic strategies t...

Aging is an elusive property of life, and many important questions about aging depend on its definition. This article proposes to draw a definition from the scientific literature on aging. First, a broad review reveals five features... more

Aging is an elusive property of life, and many important questions about aging depend on its definition. This article proposes to draw a definition from the scientific literature on aging. First, a broad review reveals five features commonly used to define aging: structural damage, functional decline, depletion, typical phenotypic changes or their cause, and increasing probability of death. Anything that can be called 'aging' must present one of these features. Then, although many conditions are not consensual instances of aging, aging is consensually described as a process of loss characterized by a rate and resulting from the counteraction of protective mechanisms against mechanisms that limit lifespan. Beyond such an abstract definition, no one has yet succeeded in defining aging by a specific mechanism of aging because of an explanatory gap between such a mechanism and lifespan, a consensual explanandum of a theory of aging. By contrast, a sound theoretical definition can be obtained by revisiting the evolutionary theory of aging. Based on this theory, aging evolves thanks to the impossibility that natural selection eliminates late traits that are neutral mainly due to decreasing selective pressure. Yet, the results of physiological research suggest that this theory should be revised to also account for the small number of different aging pathways and for the existence of mechanisms counteracting these pathways, that must, on the contrary, have been selected. A synthetic, but temporary definition of aging can finally be proposed.

https://elibrary.ru/item.asp?id=25272258 Целью данной работы является показать, что при статистической обработке экспериментальных данных с целью нахождения генотипов ( или сочетаний генотипов по разным генам ) ассоциированных с... more

https://elibrary.ru/item.asp?id=25272258 Целью данной работы является показать, что при статистической обработке экспериментальных данных с целью нахождения генотипов ( или сочетаний генотипов по разным генам ) ассоциированных с долголетием весьма желательно: 1. Всегда проводить не только анализ данных для мужчин и женщин вместе (что допустимо, когда распределение генотипов для лиц женского и мужского пола одинаково), но и проводить весь анализ для мужчин и для женщин в отдельности, 2. Использовать методы поиска генотипов ассоциированных с долголетием, предложенные автором данной работы. На основе экспериментальных исследований О.С. Глотова приводятся некоторые результаты поиска статистической связи генотипа 5./5 минисателлитного повтора в интроне 4 гена NOS3 с дожитием мужчин Северо-западного региона России до определённого возраста.
The purpose of this work is to show that it is very desirable for the purpose
of the presence of genotype (or the combinations of genotype on the different
genes) of those associated with the longevity: to always carry out not only data
analysis for the men and women together (which is permissible, when genotype
distribution for the persons of feminine and masculine sex is equal), but
also to carry out entire analysis for the men and for the women individually;
to use methods of the search for the genotype associated with the longevity,
proposed by the author of this work. On the basis of the experimental studies of
O.S. Glotov are given some results of the search for the statistical connection
of genotype 5. /5 minisatellite in the fourth intron of gene NOS3 with longevity
of the men of the North Western region of Russia. Keywords:
longevity; false-negative result; gene NOS3; data; intron; NOS34b/4a; minisatellite.
https://elibrary.ru/item.asp?id=25272258
КЛЮЧЕВЫЕ СЛОВА:
ДОЛГОЛЕТИЕ, LONGEVITY, ЛОЖНООТРИЦАТЕЛЬНЫЙ РЕЗУЛЬТАТ, ГЕН NOS3, GENE NOS3, ДАННЫЕ, DATA, ИНТРОН, INTRON, NOS34B/4A, МИНИСАТЕЛЛИТ, MINISATELLITE, FALSE-NEGATIVE RESULT
Проверка по критерию Уилконсона, о которой говорится в конце этой статьи, проведена в работе Федоров, Д. А. Проверка гипотезы о случайном характере увеличения с возрастом частоты генотипа 5./5 27bp VNTR intron4 гена NOS3 у мужчин Северо-западного региона России c помощью непараметрического парного критерия знаковых рангов/ Чебоксары, 2023.С. 99-102. DOI: 10.31483/r-107114 EDN FSLUKE., 2023
https://www.elibrary.ru/item.asp?id=53980208

Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span. However, it is uncertain which tissues exhibit reduced IGF-1 signals in the... more

Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span. However, it is uncertain which tissues exhibit reduced IGF-1 signals in the PappA(À/À) mouse, and whether effects of this mutation parallel those of mutations that diminish IGF-1 in serum. Across a panel of 21 tissues, we used RT-PCR to evaluate the effects of the PappA(À/À) mutation on expression of Igfbp5, which served as an in vivo indicator of IGF-1 signaling. Among these tissues, expression of Igfbp5 was significantly reduced by PappA(À/À) only in kidney. A broader survey of IGF-associated genes in six organs identified five other genes responsive to PappA(À/À) in kidney, with stronger effects in this organ relative to other tissues. Renal expression of Irs1 and Mt1 was increased by PappA(À/À) as well as by mutations that reduce IGF-1 in serum (i.e., Ghr(À/À), Pit1(dw/dw) and Prop1(df/df)), and we demonstrate that expression of these genes is regulated by growth hormone-treatment and calorie restriction. These results provide in vivo data on an important new model of mammalian aging, and characterize both similar and contrasting expression patterns between long-lived mice with reduced local IGF-1 availability and diminished IGF-1 in serum.

Aging can be characterized as a time dependent decline of maximal functionality that affects tissues and organs of the whole body. Such is induced by the progressive loss of redundant components and leads to an increased susceptibility to... more

Aging can be characterized as a time dependent decline of maximal functionality that affects tissues and organs of the whole body. Such is induced by the progressive loss of redundant components and leads to an increased susceptibility to disease and risk of death. Regarding the aging of skeletal muscle, it has been pointed out that mitochondria is a key factor behind the loss of redundancy and functionality, since this organelle has a major role in cellular homeostasis particularly at the level of the bioenergetic status. Decreased activities of the mitochondrial electron transport chain complexes and an increased release of reactive oxygen species from mitochondria are well documented with age; it is suggested that the mitochondrial loss of function results from the increased oxidative damage to proteins, lipids, and DNA of this organelle. However, it is important to be aware that the mitochondrial loss of function could also be a consequence, rather than a cause, of the cellular deterioration with age, which compromises mitochondrial biogenesis, mitochondrial protein turnover and autophagocytosis of damaged mitochondria. In this review several topics will be addressed regarding the age-related loss of skeletal muscle redundancy associated with mitochondrial dysfunction, emphasizing hypotheses for underlying mechanisms. In addition, we discuss some of the cellular mechanisms that can be pointed out as being responsible for the age-related mitochondrial dysfunction.

WRN is a RecQ helicase with an associated exonuclease activity important in DNA metabolism, including DNA replication, repair and recombination. In humans, deficiencies in WRN function cause the segmental progeroid Werner syndrome (WS),... more

WRN is a RecQ helicase with an associated exonuclease activity important in DNA metabolism, including DNA replication, repair and recombination. In humans, deficiencies in WRN function cause the segmental progeroid Werner syndrome (WS), in which patients show premature onset of many hallmarks of normal human ageing. At the cellular level, WRN loss results in rapid replicative senescence, chromosomal instability and sensitivity to various DNA damaging agents including the topoisomerase inhibitor, camptothecin (CPT). Here, we investigate the potential of using either transient or stable WRN knockdown as a means of sensitising cells to CPT. We show that targeting WRN mRNA for degradation by either RNAi or hammerhead ribozyme catalysis renders human fibroblasts as sensitive to CPT as fibroblasts derived from WS patients, and furthermore, we find altered cell cycle transit and nucleolar destabilisation in these cells following CPT treatment. Such WS-like phenotypes are observed despite very limited decreases in total WRN protein, suggesting that levels of WRN protein are rate-limiting for the cellular response to camptothecin. These findings have major implications for development of anti-WRN agents that may be useful in sensitising tumour cells to clinically relevant topoisomerase inhibitors.

DNA methylation contributes to the control of gene expression and plays an essential role in cellular physiology. Well-defined patterns of DNA methylation are established and fixed during embryonic development, and changes in these... more

DNA methylation contributes to the control of gene expression and plays an essential role in cellular physiology. Well-defined patterns of DNA methylation are established and fixed during embryonic development, and changes in these patterns may be a contributing factor in developmental disorders, cancer and aging. Not least the possibility of using DNA methylation as a marker for disease has created a strong need for techniques to detect and measure DNA methylation. Different techniques provide information on DNA methylation at different levels, spanning from genome-wide methylation content to methylation of single residues in specific genes. The limitations of individual techniques strongly affect interpretation of data. In this review, we discuss some general themes in DNA methylation analysis and outline the basic principles of current key techniques. We discuss the advantages and disadvantages of these techniques, including potential artifacts and pitfalls, and suggest some over...

Biological ageing can be tentatively defined as an intrinsic and inevitable degradation of biological function that accumulates over time at every level of biological organisation from molecules to populations. Senescence is characterised... more

Biological ageing can be tentatively defined as an intrinsic and inevitable degradation of biological function that accumulates over time at every level of biological organisation from molecules to populations. Senescence is characterised by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. With advancing age, all components of the human body undergo these cumulative, universal, progressive, intrinsic and deleterious (CUPID) changes. Although ageing is not a disease per se, age is the main risk factor for the development of a panoply of age-related diseases. From a mechanistic perspective, a myriad of molecular processes and components of ageing can be studied. Some of them seem especially important and they are referred to as the hallmarks of ageing. There is compelling evidence that senescence has evolved as an emergent metaphenomenon that originates in the difficulty in maintaining homeodynamics in biological systems. From an evolutionary perspective, senescence is the inevitable outcome of an evolutionarily derived equilibrium between the amount of resources devoted to somatic maintenance and the amount of resources devoted to sexual reproduction. Single-target , single-molecule and disease-oriented approaches to ageing are severely limited because they neglect the dynamic, interactive and networking nature of life. These limitations notwithstanding, many authors promote single-target and disease-oriented approaches to senescence, e.g. repurposed drugs, claiming that these methods can enhance human health and longevity. Senescence is neither a disease nor a monolithic process. In this review, the limitations of these methods are discussed. The current state of biogerontology is also summarised.

Cell senescence is an artificially reversible condition activated by various factors and characterised by replicative senescence and a stereotyped general alteration of cell functions, including extra-cellular secretions. The number of... more

Cell senescence is an artificially reversible condition activated by various factors and characterised by replicative senescence and a stereotyped general alteration of cell functions, including extra-cellular secretions. The number of senescent cells increases with age and contributes strongly to the manifestations of aging. For these reasons, research is under way to obtain “senolytic” compounds, defined as drugs that eliminate senescent cells and therefore reduce aging decay, as already shown in some experiments on animal models.
This objective is analysed in the context of the programmed aging paradigm, as described by the mechanisms of the subtelomere-telomere theory. In this regard, the positive effects of the elimination of senescent cells and the limits of this method are advanced. For comparison, the positive effects and limits of telomerase activation are also analysed, and the same is done for the combined action of the two methods and the possible association of opportune gene modifications. The ethical issues regarding these actions are also outlined.