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diff --git a/gnqa/paper1_eval/src/data/responses/aging/experts/07.json b/gnqa/paper1_eval/src/data/responses/aging/experts/07.json new file mode 100644 index 0000000..2ff5d59 --- /dev/null +++ b/gnqa/paper1_eval/src/data/responses/aging/experts/07.json @@ -0,0 +1,402 @@ +{ + "created_at": "2024-05-31T20:55:47.964141Z", + "data": { + "amplify": false, + "answer": "The aging process is caused by a combination of factors including genetic influences, environmental conditions, and stochastic processes. It involves the accumulation of molecular damage, mutations, incomplete repair, and genetic programs. Other factors include wear and tear on cells, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown. Aging is also associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes.", + "context": { + "18e216d9-ea5c-4dfe-a30d-632163fcf39e": [ + { + "document_id": "18e216d9-ea5c-4dfe-a30d-632163fcf39e", + "text": "\n\nThere are multiple definitions of the aging process.Aging may be perceived as the random, systemic loss of molecular fidelity that, after reproductive maturity, accumulates to levels that eventually exceed tissue repair, turnover, or maintenance capacity (Hayflick 2004).The underlying molecular mechanisms of aging remain a subject of debates (de Magalhaes et al. 2009): tissue deterioration might not be programmed, being just a function of increase in entropy (Hayflick 2004).No genes are necessary to drive a stochastic process; however, there are genes that act to prevent an organism from destruction and disorganization.It may be due to the absence of specific disease-causing alleles or due to the presence of favorable alleles (Halaschek-Wiener et al. 2009).These genes may inhibit entropy, regulate inflammation, maintain DNA repair (such as telomere maintenance factors), or provide antioxidant functions (e.g., antagonists of reactive oxygen species).As healthy cells adapt to degeneration, differential expression of genes with age may indicate a transcriptional response to aging rather than a deleterious mechanism of aging per se (de Magalhaes et al. 2009).It might be postulated that there exist alleles that confer a pleiotropic effect on structure and function during aging (Lunetta et al. 2007).These alleles should regulate the ability of an organism to withstand challenging endogenous and exogenous influences." + } + ], + "1ccb0d11-1c88-4b08-b40d-4039a954745f": [ + { + "document_id": "1ccb0d11-1c88-4b08-b40d-4039a954745f", + "text": "Why does ageing evolve? The intrinsic decline in function that occurs during ageing appears to be caused by the accumulation of damage, particularly at the molecular level.As far as we know, no genes have evolved specifically because they cause damage to accumulate, and the evolution of ageing can therefore be understood only as a side-effect of other causes of evolutionary change.The mechanisms by which ageing can evolve were first elucidated by J.B.S. Haldane [14], P.B. Medawar [15] and G.C. Williams [16].Extrinsic hazards from disease, predation and accidents mean that even potentially immortal organisms will die.Genetic effects that become apparent only later in life encounter a reduced force of natural selection, because not all their bearers will survive to express them.Haldane pointed out that late-onset genetic diseases in humans, such as Huntington's disease, encounter only weak selection, because most reproduction is complete by the age of onset [14].Ageing could therefore result from the accumulation under mutation pressure of age-specific, deleterious mutations.In addition, if some mutations have pleiotropic effects, with beneficial effects in youth, such as high fecundity, but also with a higher subsequent rate of ageing, then they could be incorporated into the population by natural selection, which will act more strongly on the early, beneficial effect.Thus, variation in the rate of ageing would result from the readjustment of a tradeoff between youthful benefits and the subsequent rate of ageing.Both processes imply that faster ageing will evolve where the extrinsic hazard to adults is greatest, a hypothesis in general supported by the data [1,2,17]." + } + ], + "4f010a74-a9b4-4538-94f7-ae8f35c8b96e": [ + { + "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e", + "text": "A. Theories\n\nIn looking back at the development of aging studies, we can see that it did not follow a straight or logical course.On the contrary, it can be compared with the flow of several convergent streams winding in their course.To date, numerous proposals have been made for the paradigm of aging.These include Hayflick's contributions (153) on programmed cellular incapacitation derived from flbroblast studies, a decrease in immunologic response, deleterious endocrinological changes, nuclear somatic gene mutation, mitochondrial somatic gene mutation, oxygen free radical damage to proteins and nucleic acids, molecular instabilities, molecular cross-linking, glycation reactions, and so on.There is little doubt that many of these factors contribute to the overall aging, but what are primary causes, and what are secondary outcomes?" + } + ], + "4f709611-ea0b-4bcc-a634-df5d518ccb54": [ + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "text": "Ageing Is Adjusted by Genetic, Environmental, and Stochastic Processes\n\nEnough evidence suggests that ageing is the result of different events such as molecular damage, mutations, incomplete repair, genetic programs, and continued development, among others [16].These events, in turn, are caused by genetic factors, environmental conditions, and even stochastic factors, which are mentioned below in this chapter." + }, + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "text": "\n\nDifferent stochastic theories of ageing focus on specific mechanisms that may lead to ageing.The catastrophic error theory poses that the accumulation of errors in protein synthesis causes damage in cell function.The theory of cross-linking holds this process between proteins and other macromolecules responsible for ageing, while the theory of free radicals suggests that ageing is the result of inadequate protection against cell and tissue damage by free radicals and oxidative stress throughout life.Finally, the wear-and-tear theory poses that the cumulative damage that eventually leads to ageing and death is, in fact, the result of the continuous functioning of vital processes, during which stochastic errors gradually arise." + }, + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "text": "Introduction\n\nAging is a natural and irreversible process characterized by a progressive decay in physiological, biochemical, and structural functions of individuals.Aging is a multifactorial process that can be affected by two main factors: environmental and genetic.Environmental factors are nutrition, pathologies, pollution exposure, physical activity, and microbiota, while genetic factors are issues that have been associated with antioxidant and DNA damage responses, the fidelity of genetic information transfer, the efficiency of protein degradation, the extent of cellular responsiveness to stress, the mechanisms of epigenetic regulation, and the ability to elongate telomeres.All of them can determine how fast we age.Traditionally, aging studies had used several model organisms, from yeast to mammals, especially rodents (rats and mice).Most of the studies are made under controlled conditions, where only a few variables are observed, and the subjects are members of the same strain with the same genetic backgrounds or the same mutations.The information that so far has been obtained about aging has helped us to describe different factors that influence this process and that are the fundamental concepts of the various theories of aging.However, these theories do not fully explain the aging process in the different models of aging study.This is the case of the study of aging in humans, where it is very difficult to control the environmental and genetic variables.That is why issues haven't been solved such as the following: How does time influence aging?When do we start to age?How do we know we are old?Is it possible to delay aging?Those and more questions are the cornerstones for aging studies.Biological aging has been associated with the decrease in the repair and regeneration capacity of tissues and organs; it is a time-dependent process.This reduction can be observed by an increase in the acquisition of diseases and functional and reproductive disability, which eventually lead to death.On the other hand, it has been observed that in humans, people with the same chronological age exhibit different trajectories in the decrease of physiological functions associated with biological aging and what complicates the understanding of the molecular and physiological phenomena that drive the complex and multifactorial processes that underlie biological aging in humans." + } + ], + "5030cbc8-e02c-4e3a-8cbc-0156ce123c99": [ + { + "document_id": "5030cbc8-e02c-4e3a-8cbc-0156ce123c99", + "text": "\nThe underlying cause of aging remains one of the central mysteries of biology.Recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues.This Review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming.By defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges." + } + ], + "5e157c2e-91b8-466d-a9fd-f91f8f432f0c": [ + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "text": "\n\nAging does not happen in a vacuum.Aging must be the result of changes that occur in molecules that have existed at one time with no age changes.It is the state of these pre-existing molecules that governs longevity determination.The pre-existing state is, as I have already described, maintained by repair and turnover systems that themselves eventually succumb to irreparable age changes.Longevity determination is the state of all molecules prior to succumbing to irreparable loss of molecular structure." + }, + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "text": "\n\nBiological aging is more than simply the occurrence of random changes in molecules.It also includes the role of the many repair systems found within cells.Thus, a more complete, but less concise, explanation of the first causes of aging in biological systems is the following:" + } + ], + "5f434783-db8a-409e-a1c6-1dc1c5e2ba1c": [ + { + "document_id": "5f434783-db8a-409e-a1c6-1dc1c5e2ba1c", + "text": "U\n\nnderstanding the deleterious processes that cause aging has been a human endeavor ever since we figured out that we grew old and that we didn't like it.Many hypotheses have been proposed to explain the root cause of aging (1).One broad-based hypothesis is that generalized homeostatic failure leads to age-related decline.Although notions of time-and use-related deterioration may be applicable to mechanical objects, they fall short as analogies to biological systems because energy input should theoretically maintain living systems indefinitely.Yet, despite the regenerative potential of biological organisms, progressive deterioration accompanies postmaturational aging.That the organism's repair capabilities cannot keep up with wear and tear is, according to evolutionary theory, explained by the inevitable declining force of natural selection with age.According to this reasoning, there is no selective advantage to maintaining somatic cells in perfect order much beyond reproductive maturation (1).Hence, a long life depends on the timing of maturation and the quality of somatic cell maintenance." + }, + { + "document_id": "5f434783-db8a-409e-a1c6-1dc1c5e2ba1c", + "text": "\n\nWear and tear on the DNA often has been touted as a possible basis for our progressive age-related decline.Supporting this notion is the work of de Boer et al. (2) reported on page 1276 of this week's issue.They reveal important evidence for imperfect genome maintenance of DNA damage as a possible causal factor in aging.Harman, with his \"free radical theory of aging\" (3), was the first to propose that metabolic by-products called reactive oxygen species (ROS) continually damage cellular macromolecules, including DNA.Incomplete repair of such damage would lead to its accumulation over time and eventually result in age-related deterioration.A number of observations support the free radical theory, including the discovery that dietary restriction delays aging and extends life-span in a wide range of rodents and other species, possibly by reducing free radical damage.The notion that genomic DNA could be a major target of continual free radical attack over time is supported by the recent observation that genetic lesions accumulate with age and that dietary restriction reduces this accumulation in rodents (4).In addition, deletion of p66 shc , a signaling protein that maintains oxidant levels, increases resistance to oxidative damage and extends the life-span of mice (5)." + } + ], + "606c59c5-5ae4-47e9-b3eb-58afa55669d1": [ + { + "document_id": "606c59c5-5ae4-47e9-b3eb-58afa55669d1", + "text": "Instead, aging is expected to\nbe a pervasive failure of adaptation across most, if not all, of the physiological mechanisms\nthat sustain survival and reproduction among young individuals. For this reason, evolutionary biologists have generally been skeptical of proposals that attribute “the cause of\naging” to any one physiological mechanism or gene for aging or programmed death. Although common genetic pathways might be identified that contribute to aging among a\nvariety of organisms (cf." + } + ], + "846ae0a9-165f-4b25-8bcb-310c7da5eb44": [ + { + "document_id": "846ae0a9-165f-4b25-8bcb-310c7da5eb44", + "text": "Background\n\nAging is a complex process characterized by the progressive degeneration of a healthy phenotype and correlated with a decline in the ability to withstand cellular stress and damage.The subject of investigation for decades, the underlying molecular genetic causes of and responses to aging remain an area of active study.Research from model systems has characterized a range of physiological and molecular phenotypes associated with aging.These include genomic instability caused by accumulation of DNA damage, dysregulation of repair mechanisms, and telomere attrition; epigenetic alterations; dysregulation of transcription; loss of proteostasis; cellular senescence; and deregulated nutrient sensing, metabolic pathways, and energy use (reviewed in [1]).Separating causation from correlation between these phenotypes and aging remains a challenge, however." + } + ], + "870798fd-2c26-4819-9403-fe52836770eb": [ + { + "document_id": "870798fd-2c26-4819-9403-fe52836770eb", + "text": "Introduction\n\nUnderstanding what actually causes ageing remains admittedly a fundamental and fascinating problem in biology [1].Experimental data accumulated in the last three decades have led to the identification of various environmental and genetic factors, as well as chemical substances that influence lifespan in divergent eukaryotic species [1,2].Organisms normally age faster and hence live shorter under stress conditions that can lead to the generation of DNA mutations and, often as a consequence of mutations, damaged cytoplasmic constituents (including injured proteins, lipids, carbohydrates and organelles).Such types of damage can interfere with cellular functioning; thereby, they should be eliminated by effective repair and self-cleaning mechanisms to maintain cellular homeostasis.These mechanisms include DNA repair pathways, molecular chaperons, as well as the proteasome-ubiquitin system and lysosome-mediated autophagy, the main forms of cellular self-degradation [3].This has led to the attractive model that the gradual, lifelong accumulation of unrepaired cellular damage drives the ageing process and determines the incidence of age-related fatal diseases [4,5]." + } + ], + "996e02bf-91b2-4e81-89ba-1f661dfc662a": [ + { + "document_id": "996e02bf-91b2-4e81-89ba-1f661dfc662a", + "text": "\n\nIn conclusion, aging may not be primarily due to damage accumulating from the basic biochemical reactions that make up life but rather the result of the developmental program or of changes brought about by it.Our hypothesis is that the timing of development regulates the rate of aging among mammals, with a subset of developmental mechanisms determining the pace and causing most agerelated changes.Maybe people change as they grow old due to the same mechanisms that drive changes throughout the earlier stages in life." + } + ], + "a440a3fa-74e7-4fd8-8a7f-d0391300d6ed": [ + { + "document_id": "a440a3fa-74e7-4fd8-8a7f-d0391300d6ed", + "text": "Instead, aging is expected to\nbe a pervasive failure of adaptation across most, if not all, of the physiological mechanisms\nthat sustain survival and reproduction among young individuals. For this reason, evolutionary biologists have generally been skeptical of proposals that attribute “the cause of\naging” to any one physiological mechanism or gene for aging or programmed death. Although common genetic pathways might be identified that contribute to aging among a\nvariety of organisms (cf." + } + ], + "a6bc2efd-61a7-4e07-ad5c-49234aa89431": [ + { + "document_id": "a6bc2efd-61a7-4e07-ad5c-49234aa89431", + "text": "\n\nIn 2021, Science published a special issue entitled \"125 Questions: Exploration and Discovery.\" One of these 125 questions was \"Can we stop ourselves from aging? \"The U.S. National Institute on Aging (NIA) at the National Institutes of Health (NIH) states that \"aging is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes.\" Although geneticists and epidemiologists have long debated the relative importance of the role played by genotype or the environment in the development of age-related diseases, it is apparent that both can play substantial roles in this process [6,7].However, most etiological studies have concentrated on the role of genotype and have considered the environment to play a secondary role.Nevertheless, an analysis of GBD data showed that nearly 50% of deaths worldwide are attributable to environmental exposure, primarily exposure to airborne particulates (including household air pollution and occupational exposure; 14% of all deaths), smoking and secondhand smoke (13%), plasma sodium concentrations (6%), and alcohol consumption (5%) [8].In contrast, a recent analysis of 28 chronic diseases in identical twins showed that the genetic-related risks of developing one of five age-related diseases were 33.3%, 10.6%, 36.3%, 19.5%, and 33.9% for AD, PD, CAD, COPD, and T2DM, respectively, with a mean of only 26% [9].The results of over 400 genome-wide association studies (GWASs) have also elucidated that the heritability of degenerative diseases is only approximately 10% [10,11].Consequently, nongenetic drivers, such as environmental factors, are now recognized as major risk factors for age-related diseases.The contributions of environmental factors to the development of age-related diseases can be revealed by analyses of all of the factors to which individuals are exposed in their life and the relationships between these exposures and age-related diseases [12,13]." + } + ], + "ab6a47ba-2131-4fc5-be5e-b81dd80d2a65": [ + { + "document_id": "ab6a47ba-2131-4fc5-be5e-b81dd80d2a65", + "text": "Introduction\n\nThe fundamental manifestation of the aging process is a progressive decline in the functional maintenance of tissue homeostasis and an increasing propensity to degenerative diseases and death [1].It has attracted significant interest to study the underlying mechanisms of aging, and many theories have been put forward to explain the phenomenon of aging.There is an emerging consensus that aging is a multifactorial process, which is genetically determined and influenced epigenetically by environment [2].Most aging theories postulate a single physiological cause of aging, and likely these theories are correct to a certain degree and in certain aspects of aging." + } + ], + "ca76f85d-9f72-4e15-8ba9-3bf94308c449": [ + { + "document_id": "ca76f85d-9f72-4e15-8ba9-3bf94308c449", + "text": "\n\nMany factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics." + } + ], + "f4dd6a1d-062b-42bc-8e22-83fcb3135578": [ + { + "document_id": "f4dd6a1d-062b-42bc-8e22-83fcb3135578", + "text": "\n\nTrying to explain aging in terms of a singular process would be in conflict with evolutionary theory.Even if loss of genome sequence integrity was the most conserved cause of aging, already active in the first replicators (Vijg, 2007), natural selection would allow a multitude of mutations with late adverse effects to accumulate in the germline, many of which would be positively selected for because of their beneficial effects early in life (Williams, 1957), In this respect, somatic mutation accumulation could be a conserved, inevitable cause of aging but superposed on multiple other processes that usually cause the earlier demise of an individual." + } + ] + }, + "data_source": [ + { + "document_id": "ca76f85d-9f72-4e15-8ba9-3bf94308c449", + "section_type": "main", + "text": "\n\nMany factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics." + }, + { + "document_id": "870798fd-2c26-4819-9403-fe52836770eb", + "section_type": "main", + "text": "Introduction\n\nUnderstanding what actually causes ageing remains admittedly a fundamental and fascinating problem in biology [1].Experimental data accumulated in the last three decades have led to the identification of various environmental and genetic factors, as well as chemical substances that influence lifespan in divergent eukaryotic species [1,2].Organisms normally age faster and hence live shorter under stress conditions that can lead to the generation of DNA mutations and, often as a consequence of mutations, damaged cytoplasmic constituents (including injured proteins, lipids, carbohydrates and organelles).Such types of damage can interfere with cellular functioning; thereby, they should be eliminated by effective repair and self-cleaning mechanisms to maintain cellular homeostasis.These mechanisms include DNA repair pathways, molecular chaperons, as well as the proteasome-ubiquitin system and lysosome-mediated autophagy, the main forms of cellular self-degradation [3].This has led to the attractive model that the gradual, lifelong accumulation of unrepaired cellular damage drives the ageing process and determines the incidence of age-related fatal diseases [4,5]." + }, + { + "document_id": "5f434783-db8a-409e-a1c6-1dc1c5e2ba1c", + "section_type": "main", + "text": "U\n\nnderstanding the deleterious processes that cause aging has been a human endeavor ever since we figured out that we grew old and that we didn't like it.Many hypotheses have been proposed to explain the root cause of aging (1).One broad-based hypothesis is that generalized homeostatic failure leads to age-related decline.Although notions of time-and use-related deterioration may be applicable to mechanical objects, they fall short as analogies to biological systems because energy input should theoretically maintain living systems indefinitely.Yet, despite the regenerative potential of biological organisms, progressive deterioration accompanies postmaturational aging.That the organism's repair capabilities cannot keep up with wear and tear is, according to evolutionary theory, explained by the inevitable declining force of natural selection with age.According to this reasoning, there is no selective advantage to maintaining somatic cells in perfect order much beyond reproductive maturation (1).Hence, a long life depends on the timing of maturation and the quality of somatic cell maintenance." + }, + { + "document_id": "846ae0a9-165f-4b25-8bcb-310c7da5eb44", + "section_type": "main", + "text": "Background\n\nAging is a complex process characterized by the progressive degeneration of a healthy phenotype and correlated with a decline in the ability to withstand cellular stress and damage.The subject of investigation for decades, the underlying molecular genetic causes of and responses to aging remain an area of active study.Research from model systems has characterized a range of physiological and molecular phenotypes associated with aging.These include genomic instability caused by accumulation of DNA damage, dysregulation of repair mechanisms, and telomere attrition; epigenetic alterations; dysregulation of transcription; loss of proteostasis; cellular senescence; and deregulated nutrient sensing, metabolic pathways, and energy use (reviewed in [1]).Separating causation from correlation between these phenotypes and aging remains a challenge, however." + }, + { + "document_id": "996e02bf-91b2-4e81-89ba-1f661dfc662a", + "section_type": "main", + "text": "\n\nIn conclusion, aging may not be primarily due to damage accumulating from the basic biochemical reactions that make up life but rather the result of the developmental program or of changes brought about by it.Our hypothesis is that the timing of development regulates the rate of aging among mammals, with a subset of developmental mechanisms determining the pace and causing most agerelated changes.Maybe people change as they grow old due to the same mechanisms that drive changes throughout the earlier stages in life." + }, + { + "document_id": "5030cbc8-e02c-4e3a-8cbc-0156ce123c99", + "section_type": "abstract", + "text": "\nThe underlying cause of aging remains one of the central mysteries of biology.Recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues.This Review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming.By defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges." + }, + { + "document_id": "606c59c5-5ae4-47e9-b3eb-58afa55669d1", + "section_type": "main", + "text": "Instead, aging is expected to\nbe a pervasive failure of adaptation across most, if not all, of the physiological mechanisms\nthat sustain survival and reproduction among young individuals. For this reason, evolutionary biologists have generally been skeptical of proposals that attribute “the cause of\naging” to any one physiological mechanism or gene for aging or programmed death.\n Although common genetic pathways might be identified that contribute to aging among a\nvariety of organisms (cf." + }, + { + "document_id": "a440a3fa-74e7-4fd8-8a7f-d0391300d6ed", + "section_type": "main", + "text": "Instead, aging is expected to\nbe a pervasive failure of adaptation across most, if not all, of the physiological mechanisms\nthat sustain survival and reproduction among young individuals. For this reason, evolutionary biologists have generally been skeptical of proposals that attribute “the cause of\naging” to any one physiological mechanism or gene for aging or programmed death.\n Although common genetic pathways might be identified that contribute to aging among a\nvariety of organisms (cf." + }, + { + "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e", + "section_type": "main", + "text": "A. Theories\n\nIn looking back at the development of aging studies, we can see that it did not follow a straight or logical course.On the contrary, it can be compared with the flow of several convergent streams winding in their course.To date, numerous proposals have been made for the paradigm of aging.These include Hayflick's contributions (153) on programmed cellular incapacitation derived from flbroblast studies, a decrease in immunologic response, deleterious endocrinological changes, nuclear somatic gene mutation, mitochondrial somatic gene mutation, oxygen free radical damage to proteins and nucleic acids, molecular instabilities, molecular cross-linking, glycation reactions, and so on.There is little doubt that many of these factors contribute to the overall aging, but what are primary causes, and what are secondary outcomes?" + }, + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "section_type": "main", + "text": "Ageing Is Adjusted by Genetic, Environmental, and Stochastic Processes\n\nEnough evidence suggests that ageing is the result of different events such as molecular damage, mutations, incomplete repair, genetic programs, and continued development, among others [16].These events, in turn, are caused by genetic factors, environmental conditions, and even stochastic factors, which are mentioned below in this chapter." + }, + { + "document_id": "a6bc2efd-61a7-4e07-ad5c-49234aa89431", + "section_type": "main", + "text": "\n\nIn 2021, Science published a special issue entitled \"125 Questions: Exploration and Discovery.\" One of these 125 questions was \"Can we stop ourselves from aging? \"The U.S. National Institute on Aging (NIA) at the National Institutes of Health (NIH) states that \"aging is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes.\" Although geneticists and epidemiologists have long debated the relative importance of the role played by genotype or the environment in the development of age-related diseases, it is apparent that both can play substantial roles in this process [6,7].However, most etiological studies have concentrated on the role of genotype and have considered the environment to play a secondary role.Nevertheless, an analysis of GBD data showed that nearly 50% of deaths worldwide are attributable to environmental exposure, primarily exposure to airborne particulates (including household air pollution and occupational exposure; 14% of all deaths), smoking and secondhand smoke (13%), plasma sodium concentrations (6%), and alcohol consumption (5%) [8].In contrast, a recent analysis of 28 chronic diseases in identical twins showed that the genetic-related risks of developing one of five age-related diseases were 33.3%, 10.6%, 36.3%, 19.5%, and 33.9% for AD, PD, CAD, COPD, and T2DM, respectively, with a mean of only 26% [9].The results of over 400 genome-wide association studies (GWASs) have also elucidated that the heritability of degenerative diseases is only approximately 10% [10,11].Consequently, nongenetic drivers, such as environmental factors, are now recognized as major risk factors for age-related diseases.The contributions of environmental factors to the development of age-related diseases can be revealed by analyses of all of the factors to which individuals are exposed in their life and the relationships between these exposures and age-related diseases [12,13]." + }, + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "section_type": "main", + "text": "Introduction\n\nAging is a natural and irreversible process characterized by a progressive decay in physiological, biochemical, and structural functions of individuals.Aging is a multifactorial process that can be affected by two main factors: environmental and genetic.Environmental factors are nutrition, pathologies, pollution exposure, physical activity, and microbiota, while genetic factors are issues that have been associated with antioxidant and DNA damage responses, the fidelity of genetic information transfer, the efficiency of protein degradation, the extent of cellular responsiveness to stress, the mechanisms of epigenetic regulation, and the ability to elongate telomeres.All of them can determine how fast we age.Traditionally, aging studies had used several model organisms, from yeast to mammals, especially rodents (rats and mice).Most of the studies are made under controlled conditions, where only a few variables are observed, and the subjects are members of the same strain with the same genetic backgrounds or the same mutations.The information that so far has been obtained about aging has helped us to describe different factors that influence this process and that are the fundamental concepts of the various theories of aging.However, these theories do not fully explain the aging process in the different models of aging study.This is the case of the study of aging in humans, where it is very difficult to control the environmental and genetic variables.That is why issues haven't been solved such as the following: How does time influence aging?When do we start to age?How do we know we are old?Is it possible to delay aging?Those and more questions are the cornerstones for aging studies.Biological aging has been associated with the decrease in the repair and regeneration capacity of tissues and organs; it is a time-dependent process.This reduction can be observed by an increase in the acquisition of diseases and functional and reproductive disability, which eventually lead to death.On the other hand, it has been observed that in humans, people with the same chronological age exhibit different trajectories in the decrease of physiological functions associated with biological aging and what complicates the understanding of the molecular and physiological phenomena that drive the complex and multifactorial processes that underlie biological aging in humans." + }, + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "section_type": "main", + "text": "\n\nBiological aging is more than simply the occurrence of random changes in molecules.It also includes the role of the many repair systems found within cells.Thus, a more complete, but less concise, explanation of the first causes of aging in biological systems is the following:" + }, + { + "document_id": "18e216d9-ea5c-4dfe-a30d-632163fcf39e", + "section_type": "main", + "text": "\n\nThere are multiple definitions of the aging process.Aging may be perceived as the random, systemic loss of molecular fidelity that, after reproductive maturity, accumulates to levels that eventually exceed tissue repair, turnover, or maintenance capacity (Hayflick 2004).The underlying molecular mechanisms of aging remain a subject of debates (de Magalhaes et al. 2009): tissue deterioration might not be programmed, being just a function of increase in entropy (Hayflick 2004).No genes are necessary to drive a stochastic process; however, there are genes that act to prevent an organism from destruction and disorganization.It may be due to the absence of specific disease-causing alleles or due to the presence of favorable alleles (Halaschek-Wiener et al. 2009).These genes may inhibit entropy, regulate inflammation, maintain DNA repair (such as telomere maintenance factors), or provide antioxidant functions (e.g., antagonists of reactive oxygen species).As healthy cells adapt to degeneration, differential expression of genes with age may indicate a transcriptional response to aging rather than a deleterious mechanism of aging per se (de Magalhaes et al. 2009).It might be postulated that there exist alleles that confer a pleiotropic effect on structure and function during aging (Lunetta et al. 2007).These alleles should regulate the ability of an organism to withstand challenging endogenous and exogenous influences." + }, + { + "document_id": "4ca8d070-8b58-4bd5-86be-127089b70324", + "section_type": "main", + "text": "\n\nThe dominant theory at the time was that aging was caused by the accumulation of molecular damage generated by oxygen radicals, particularly originating from the mitochondria.Independently, Pamela Larsen and Jacques Vanfleteren exposed wild-type and age-1 mutants to oxidants (hydrogen peroxide and paraquat, respectively) (26,27).The assays were conducted in young animals over days.The long-lived mutants were resistant to oxidative stress.Moreover, age-1 mutant worms had elevated levels of the antioxidant enzymes, superoxide dismutase, and catalase activities which could be sufficient to confer oxidative stress resistance and was consistent with the oxygen radical theory of aging." + }, + { + "document_id": "42cbc297-d57c-4c1f-8d3f-f9e52748b823", + "section_type": "main", + "text": "Conclusions\n\nSkin follows the pathway of aging, whereas in addition to the internal factors, several environmental ones contribute to this process and sometimes accelerate the onset of aging in the skin.Skin functions deteriorate, and this results in the development of a palette of diseases that sometimes jeopardize life quality or even life itself.Awareness of the pathophysiology of age-associated skin diseases as well as of preventive measurements to avoid skin damage is the first step for successful, healthy aging.Genomic technologies, such as gene chips, have identified gene expression signatures associated with skin aging and have become a fundamental basis in helping to develop new skin repair products.Proteomics and metabolomics can complete the increasing knowledge in this field.Research to understand a natural phenomenon such as aging should not only be considered as a privilege of modern Western society but also as the best prevention of age-associated diseases, including cancer." + }, + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "section_type": "abstract", + "text": "\nThe belief that aging is still an unsolved problem in biology is no longer true.Of the two major classes of theories, the one class that is tenable is derivative of a single common denominator that results in only one fundamental theory of aging.In order to address this complex subject, it is necessary to first define the four phenomena that characterize the finitude of life.These phenomena are aging, the determinants of longevity, age-associated diseases, and death.There are only two fundamental ways in which age changes can occur.Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events.The weight of evidence indicates that genes do not drive the aging process but the general loss of molecular fidelity does.Potential longevity is determined by the energetics of all molecules present at and after the time of reproductive maturation.Thus, every molecule, including those that compose the machinery involved in turnover, replacement, and repair, becomes the substrate that experiences the thermodynamic instability characteristic of the aging process.However, the determinants of the fidelity of all molecules produced before and after reproductive maturity are the determinants of longevity.This process is governed by the genome.Aging does not happen in a vacuum.Aging must be the result of changes that occur in molecules that have existed at one time with no age changes.It is the state of these pre-existing molecules that governs longevity determination.The distinction between the aging process and age-associated disease is not only based on the molecular definition of aging described above but it is also rooted in several practical observations.Unlike any disease, age changes (a) occur in every multicellular animal that reaches a fixed size at reproductive maturity, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) occur in virtually all animate and inanimate matter, and (f ) have the same universal molecular etiology, that is, thermodynamic instability.Unlike aging, there is no disease or pathology that shares these six qualities.Because this critical distinction is poorly understood, there" + }, + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "section_type": "main", + "text": "\n\nDifferent stochastic theories of ageing focus on specific mechanisms that may lead to ageing.The catastrophic error theory poses that the accumulation of errors in protein synthesis causes damage in cell function.The theory of cross-linking holds this process between proteins and other macromolecules responsible for ageing, while the theory of free radicals suggests that ageing is the result of inadequate protection against cell and tissue damage by free radicals and oxidative stress throughout life.Finally, the wear-and-tear theory poses that the cumulative damage that eventually leads to ageing and death is, in fact, the result of the continuous functioning of vital processes, during which stochastic errors gradually arise." + }, + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "section_type": "main", + "text": "\n\nAging then is a catabolic process that is chance driven.Longevity determination is an anabolic process that, indirectly, is genome driven." + }, + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "section_type": "main", + "text": "\n\nThe evidence for the belief that aging is a stochastic process is, first, that everything in the universe changes or ages in space-time without being driven by a purposeful program.Second, there is no direct evidence that proves that age changes are governed by a genetic program.Finally, there is a huge body of knowledge indicating that age changes are characterized by the loss of molecular fidelity." + }, + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "section_type": "main", + "text": "\n\nAging does not happen in a vacuum.Aging must be the result of changes that occur in molecules that have existed at one time with no age changes.It is the state of these pre-existing molecules that governs longevity determination.The pre-existing state is, as I have already described, maintained by repair and turnover systems that themselves eventually succumb to irreparable age changes.Longevity determination is the state of all molecules prior to succumbing to irreparable loss of molecular structure." + }, + { + "document_id": "ab6a47ba-2131-4fc5-be5e-b81dd80d2a65", + "section_type": "main", + "text": "Introduction\n\nThe fundamental manifestation of the aging process is a progressive decline in the functional maintenance of tissue homeostasis and an increasing propensity to degenerative diseases and death [1].It has attracted significant interest to study the underlying mechanisms of aging, and many theories have been put forward to explain the phenomenon of aging.There is an emerging consensus that aging is a multifactorial process, which is genetically determined and influenced epigenetically by environment [2].Most aging theories postulate a single physiological cause of aging, and likely these theories are correct to a certain degree and in certain aspects of aging." + }, + { + "document_id": "5e157c2e-91b8-466d-a9fd-f91f8f432f0c", + "section_type": "main", + "text": "\n\nThe belief that aging is still an unsolved problem in biology is no longer true.Of the two major classes of theories, the one class that is tenable is derivative of a single common denominator that results in only one fundamental theory of aging.In order to address this complex subject, it is necessary to first define the four phenomena that characterize the finitude of life.These phenomena are aging, the determinants of longevity, age-associated diseases, and death.There are only two fundamental ways in which age changes can occur.Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events.The weight of evidence indicates that genes do not drive the aging process but the general loss of molecular fidelity does.Potential longevity is determined by the energetics of all molecules present at and after the time of reproductive maturation.Thus, every molecule, including those that compose the machinery involved in turnover, replacement, and repair, becomes the substrate that experiences the thermodynamic instability characteristic of the aging process.However, the determinants of the fidelity of all molecules produced before and after reproductive maturity are the determinants of longevity.This process is governed by the genome.Aging does not happen in a vacuum.Aging must be the result of changes that occur in molecules that have existed at one time with no age changes.It is the state of these pre-existing molecules that governs longevity determination.The distinction between the aging process and age-associated disease is not only based on the molecular definition of aging described above but it is also rooted in several practical observations.Unlike any disease, age changes (a) occur in every multicellular animal that reaches a fixed size at reproductive maturity, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) occur in virtually all animate and inanimate matter, and (f ) have the same universal molecular etiology, that is, thermodynamic instability.Unlike aging, there is no disease or pathology that shares these six qualities.Because this critical distinction is poorly understood, there" + }, + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "section_type": "main", + "text": "\n\nThus, ageing and age-related diseases are probably not mediated by a single factor or primary mechanism, but rather their result of multiple mechanisms, some of which may be genetically determined, and others may be the result of environmental exposures or stochastic.However, not all these processes are currently accounted for, and their precise contribution to ageing remains unclear.It is, therefore, necessary to further aim research efforts at identifying these connections; this may eventually lead to the development of better treatments for age-related diseases and maybe even anti-ageing strategies." + }, + { + "document_id": "489539fd-f7c5-44eb-bb58-5fc19d50a7cf", + "section_type": "main", + "text": "A common theme among many of these\ntheories is to take a reductionist approach and focus attention at the molecular level in\nhopes of understanding the aging of organisms through the aging of their components. In\nour quest to understand the aging process, we must face reality and succumb to the notion\nthat aging is a multifactorial process; therefore it’s likely that all of the aforementioned\nprocesses factor into this phenomenon.\n An important theme emerging in the field of aging research is the role of\nepigenetic alterations in aging mammalian tissues." + }, + { + "document_id": "f2b8524b-501d-4ec7-a3d7-048aab67ce05", + "section_type": "main", + "text": "Introduction\n\nDespite recent progress, human aging is a largely controversial process.Many age-related changes have been described, yet there are multiple and conflicting theories regarding what mechanism(s) drive such changes (de Magalhães, 2005).Moreover, we do not know why different species age at different paces, and there is still no proven intervention capable of delaying or postponing the human aging process (Olshansky et al ., 2002).As such, it is clear that aging is a complex, challenging phenomenon that requires extensive research using multiple, interdisciplinary approaches to unravel its puzzles." + }, + { + "document_id": "f4dd6a1d-062b-42bc-8e22-83fcb3135578", + "section_type": "main", + "text": "\n\nTrying to explain aging in terms of a singular process would be in conflict with evolutionary theory.Even if loss of genome sequence integrity was the most conserved cause of aging, already active in the first replicators (Vijg, 2007), natural selection would allow a multitude of mutations with late adverse effects to accumulate in the germline, many of which would be positively selected for because of their beneficial effects early in life (Williams, 1957), In this respect, somatic mutation accumulation could be a conserved, inevitable cause of aging but superposed on multiple other processes that usually cause the earlier demise of an individual." + }, + { + "document_id": "996e02bf-91b2-4e81-89ba-1f661dfc662a", + "section_type": "main", + "text": "\n\nThe developmental theory of aging states that the genetic mechanisms regulating the pace of aging are located in the latter; that is, they are part of the developmental program (FIGURE 1).This concept is supported by observations in a number of animals.In organisms such as the salmon or marsupials of the genus Antechinus, the neuroendocrine system-triggered by reproduction-directly causes the death of organisms (19).Other authors have argued that a morphogenetic program originates aging in response to reproductive impulses (30,38).It is dubious, however, that similar mechanisms occur in animals that rear their offspring, such as most mammals and birds.Besides, not only reproduction but a number of developmental processes have the potential to disrupt homeostasis and cause degeneration (see below).Nonetheless, Antechinus and, particularly, the remarkable physiological degeneration of the salmon after spawning demonstrate how a developmental program optimized for reproduction can trigger senescence (19)." + }, + { + "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54", + "section_type": "main", + "text": "Stochastic Factors\n\nAgeing is no longer regarded as a programmed process, but rather the result of damage accumulation, which results from stochastic (i.e.random) events or exposures [40].The variables that affect the ageing of an organism are the result of chance and must be studied from a probabilistic approach.According to the stochastic theories of ageing, random factors may induce ageing directly (by nonspecified mechanisms) and increase the probability of developing age-related diseases." + }, + { + "document_id": "a733a920-9896-4ca4-910d-d6f0184a0777", + "section_type": "main", + "text": "Introduction\n\nThe basic similarity of biological processes in living systems pleads for a general mechanism underlying the aging process.Although there is no agreement on the nature of such a unifying mechanism of aging, changes in informational biomolecules are considered to play an important role in the etiology of age-related deteriorative processes.Conceptually, molecular biological theories of aging should first be assigned to the two fundamentally different schools of aging theories, according to which aging is regarded either as a species-specific genetically determined.program or as a series of stochastic events (Schneider 1987)." + }, + { + "document_id": "5f434783-db8a-409e-a1c6-1dc1c5e2ba1c", + "section_type": "main", + "text": "\n\nWear and tear on the DNA often has been touted as a possible basis for our progressive age-related decline.Supporting this notion is the work of de Boer et al. (2) reported on page 1276 of this week's issue.They reveal important evidence for imperfect genome maintenance of DNA damage as a possible causal factor in aging.Harman, with his \"free radical theory of aging\" (3), was the first to propose that metabolic by-products called reactive oxygen species (ROS) continually damage cellular macromolecules, including DNA.Incomplete repair of such damage would lead to its accumulation over time and eventually result in age-related deterioration.A number of observations support the free radical theory, including the discovery that dietary restriction delays aging and extends life-span in a wide range of rodents and other species, possibly by reducing free radical damage.The notion that genomic DNA could be a major target of continual free radical attack over time is supported by the recent observation that genetic lesions accumulate with age and that dietary restriction reduces this accumulation in rodents (4).In addition, deletion of p66 shc , a signaling protein that maintains oxidant levels, increases resistance to oxidative damage and extends the life-span of mice (5)." + }, + { + "document_id": "aff67cef-4bf7-42dc-826b-2a259722008d", + "section_type": "abstract", + "text": "\nAs our society is growing older, the consequences of aging have begun to gain particular attention.Improvement of quality of life at old age and prevention of age-associated diseases have become the main focus of the aging research.The process of aging in humans is complex and underlies multiple influences, with the probable involvement of heritable and various environmental factors.In particular, hormones are decisively involved in the generation of aging.Over time, important circulating hormones decline due to a reduced secretion of the pituitary, the adrenal glands and the gonads or due to an intercurrent disease.Among them, serum levels of growth factors and sexual steroids show significant aging-associated changes.Within the scope of the Explorative Project 'Genetic aetiology of human longevity' supported by the German National Genome Research Network 2 (NGFN-2) an in vitro model of human hormonal aging has been developed.Human SZ95 sebocytes were maintained under a hormone-substituted environment consisting of growth factors and sexual steroids in concentrations corresponding to those circulating in 20-and in 60-year-old women.Eight hundred and ninety-nine genes showed a differential expression in SZ95 sebocytes maintained under the 20-and 60-year-old hormone mixture, respectively.Among them genes were regulated which are involved in biological processes which are all hallmarks of aging.The most significantly altered signaling pathway identified was that of the transforming growth factor-b (TGF-b).A disturbed function of this cascade has been associated with tumorigenesis, i.e. in pancreatic, prostate, intestine, breast, and uterine cancer.Interestingly, genes expressed in signaling pathways operative in age-associated diseases such as Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and amyotrophic lateral sclerosis (ALS) were also identified.These data demonstrate that skin and its appendages may represent an adequate model for aging research.Hormones interact in a complex fashion, and aging may be partly attributed to the changes in their circulating blood levels.Furthermore, a disturbed hormone status may partially act towards the manifestation of neurodegenerative diseases.Thus, these results could be a basis for an integrated and interdisciplinary approach to the analysis of the aging process." + }, + { + "document_id": "555a1533-2905-4d91-a3b6-2fca3679ab02", + "section_type": "main", + "text": "\n\nAging is an extremely complex process associated with interplay of genetic, biochemical, and metabolic factors in an organism in a given environment.Although genetic studies of various animal models suggest that even a single-gene mutation can remarkably extend lifespan (Kenyon 2005;Johnson 2006) and, thus, modulate aging, no such genes are revealed in humans so far.Given that a human organism is a much more complex system than a model organism (Christensen et al. 2006), it is evident that genetic effects on the aging process should be mediated via coordinate action of a large number of inter-related processes (Kirkwood 2011).Coordinated function is rather relevant to complex biological (Soltow et al. 2010;Slagboom et al. 2011) and genetic (Bloss et al. 2011) networks than to individual genes." + }, + { + "document_id": "a733a920-9896-4ca4-910d-d6f0184a0777", + "section_type": "main", + "text": "\n\nThe fundamental mechanisms involved in the physiological deterioration observed with age in mammalian organisms have not yet been elucidated.It appears that random alterations in informational biomolecules and in their synthesis could be the basis of such physiological changes.There is, however, a lack of knowledge with respect to the frequency and characteristics of changes introduced in the cellular molecular machinery.Moreover, the driving force initiating the generation of such alterations and the order of events in which they occur are unknown at present.In this article, data concerning the hypothesis that the aging process is associated with widespread genetic instability are reviewed in the context of the complex interactions between the three major informational biomolecules, DNA, RNA, and protein.We conclude that the results obtained to date do not rule out the possibility that genetic instability in a wide sense is a major causal factor in a number of age-related phenomena.However, it appears that new strategies based on a new technology are ultimately necessary to elucidate the alterations in the intricately interwoven patterns of molecular control that could underlie the various aspects of the aging process.A first attempt is made to formulate the problems in this field and to provide some solutions." + }, + { + "document_id": "a733a920-9896-4ca4-910d-d6f0184a0777", + "section_type": "abstract", + "text": "\nThe fundamental mechanisms involved in the physiological deterioration observed with age in mammalian organisms have not yet been elucidated.It appears that random alterations in informational biomolecules and in their synthesis could be the basis of such physiological changes.There is, however, a lack of knowledge with respect to the frequency and characteristics of changes introduced in the cellular molecular machinery.Moreover, the driving force initiating the generation of such alterations and the order of events in which they occur are unknown at present.In this article, data concerning the hypothesis that the aging process is associated with widespread genetic instability are reviewed in the context of the complex interactions between the three major informational biomolecules, DNA, RNA, and protein.We conclude that the results obtained to date do not rule out the possibility that genetic instability in a wide sense is a major causal factor in a number of age-related phenomena.However, it appears that new strategies based on a new technology are ultimately necessary to elucidate the alterations in the intricately interwoven patterns of molecular control that could underlie the various aspects of the aging process.A first attempt is made to formulate the problems in this field and to provide some solutions." + }, + { + "document_id": "98ce73c6-a53b-486f-8326-4b0bd47ec22e", + "section_type": "main", + "text": "\n\nThere are several reasons for the contention that distinguishing between biological aging and disease processes may be problematic.There is little agreement on a precise definition of aging, although many have offered general characteristics; this is usefully discussed by Arking (1998).Most scientific papers on the study of aging, basic or applied, do not offer definitions of aging as an explicit biological process separate from disease and dysfunction.Survivorship and longevity, among the most widely studied attributes of aging across species, are insufficient outcomes for the study of complex animal processes, particularly in humans or other mammals; nearly all humans die of one or more discrete, identifiable medical conditions.Further, most if not all hypothesized biological mechanisms of aging encompass concepts that have also been applied to disease causation and progression.For example, age-related shortening of chromosomal telomeres has been related both to aging processes and to carcinogenesis (Shay, 1997), as have cumulative somatic mutations (Vijg, 2000;Hernandez-Boussard et al., 1999) and age-related, progressively inefficient DNA repair processes (de Boer and Hoeijmakers, 2000).Even an environmental factor that experimentally has been shown to dramatically prolong mammalian survivorship as well as decrease the occurrence of age-related physiological change and disease, caloric restriction, has been shown to alter the rate of change in age-related gene function (Lee et al., 1999)." + }, + { + "document_id": "aff67cef-4bf7-42dc-826b-2a259722008d", + "section_type": "main", + "text": "\n\nAs our society is growing older, the consequences of aging have begun to gain particular attention.Improvement of quality of life at old age and prevention of age-associated diseases have become the main focus of the aging research.The process of aging in humans is complex and underlies multiple influences, with the probable involvement of heritable and various environmental factors.In particular, hormones are decisively involved in the generation of aging.Over time, important circulating hormones decline due to a reduced secretion of the pituitary, the adrenal glands and the gonads or due to an intercurrent disease.Among them, serum levels of growth factors and sexual steroids show significant aging-associated changes.Within the scope of the Explorative Project 'Genetic aetiology of human longevity' supported by the German National Genome Research Network 2 (NGFN-2) an in vitro model of human hormonal aging has been developed.Human SZ95 sebocytes were maintained under a hormone-substituted environment consisting of growth factors and sexual steroids in concentrations corresponding to those circulating in 20-and in 60-year-old women.Eight hundred and ninety-nine genes showed a differential expression in SZ95 sebocytes maintained under the 20-and 60-year-old hormone mixture, respectively.Among them genes were regulated which are involved in biological processes which are all hallmarks of aging.The most significantly altered signaling pathway identified was that of the transforming growth factor-b (TGF-b).A disturbed function of this cascade has been associated with tumorigenesis, i.e. in pancreatic, prostate, intestine, breast, and uterine cancer.Interestingly, genes expressed in signaling pathways operative in age-associated diseases such as Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and amyotrophic lateral sclerosis (ALS) were also identified.These data demonstrate that skin and its appendages may represent an adequate model for aging research.Hormones interact in a complex fashion, and aging may be partly attributed to the changes in their circulating blood levels.Furthermore, a disturbed hormone status may partially act towards the manifestation of neurodegenerative diseases.Thus, these results could be a basis for an integrated and interdisciplinary approach to the analysis of the aging process." + }, + { + "document_id": "489539fd-f7c5-44eb-bb58-5fc19d50a7cf", + "section_type": "main", + "text": "Poorly repaired\ndamage of chromosomal DNA, stress-related aberrations in structural enzymes or protein\nturnover, and/or deletions in mitochondrial DNA, for example, may compromise organ\nfunction and in turn limit longevity. Given the extremely complex phenotype of aging,\n\n2\nnumerous other theories such as the free radial theory of aging (Harman, 1956) and\nprotein damage accumulation theory (Levine, 2002) have been postulated in an attempt to\nexplain what aging is and why it happens." + }, + { + "document_id": "1e2d93e8-a0a4-4f4a-a470-2dfdd26fa846", + "section_type": "abstract", + "text": "\nLoss of genome maintenance may causally contribute to ageing, as exemplified by the premature appearance of multiple symptoms of ageing in a growing family of human syndromes and in mice with genetic defects in genome maintenance pathways.Recent evidence revealed a similarity between such prematurely ageing mutants and long-lived mice harbouring mutations in growth signalling pathways.At first sight this seems paradoxical as they represent both extremes of ageing yet show a similar 'survival' response that is capable of delaying age-related pathology and extending lifespan.Understanding the mechanistic basis of this response and its connection with genome maintenance would open exciting possibilities for counteracting cancer or agerelated diseases, and for promoting longevity.In Greek mythology, Klotho, Lakhesis and Atropos, the three fates, spun, wove and snipped the thread of life, an unalterable process to which both gods and humans had to submit themselves.Human efforts over recent centuries have succeeded in substantially lengthening the thread, allowing ageing to become a common feature of society.However, despite intense research, the molecular basis of the processes that cause loss of bodily functions, and degeneration of cells and tissues is still unresolved.It is widely accepted that ageing is the consequence of stochastic damage accumulation 1 .Ageing is unique in that it does not seem to be subject to evolutionary selection, as it occurs after the reproductive phase, suggesting that it may occur by default 2 .Nevertheless, it is apparent from studies in many systems that ageing is subject to regulation by evolutionarily highly conserved molecular pathways [3][4][5] .As such, damage drives functional decline with advancing age; however, the existence of universal mechanisms that are able to promote longevity may set the pace on how rapidly damage builds up and function is lost.We discuss the nature of the processes that determine the length and the quality of the thread of life woven by Lakhesis and ultimately snipped by Atropos.Damage and ageing: the DNA perspective Within the complex chemical machinery of each cell, all biomolecules (proteins, lipids and nucleic acids) are subject to indiscriminate damage caused by spontaneous reactions (mostly hydrolysis) and by numerous endogenous and exogenous reactive agents.It is therefore plausible that damage to multiple cellular constituents accounts for ageing 1 .However, damage to certain macromolecules may play a more prominent part than damage to others.The almost exclusive link between an extending class George A." + }, + { + "document_id": "1ccb0d11-1c88-4b08-b40d-4039a954745f", + "section_type": "main", + "text": "Why does ageing evolve? The intrinsic decline in function that occurs during ageing appears to be caused by the accumulation of damage, particularly at the molecular level.As far as we know, no genes have evolved specifically because they cause damage to accumulate, and the evolution of ageing can therefore be understood only as a side-effect of other causes of evolutionary change.The mechanisms by which ageing can evolve were first elucidated by J.B.S. Haldane [14], P.B. Medawar [15] and G.C. Williams [16].Extrinsic hazards from disease, predation and accidents mean that even potentially immortal organisms will die.Genetic effects that become apparent only later in life encounter a reduced force of natural selection, because not all their bearers will survive to express them.Haldane pointed out that late-onset genetic diseases in humans, such as Huntington's disease, encounter only weak selection, because most reproduction is complete by the age of onset [14].Ageing could therefore result from the accumulation under mutation pressure of age-specific, deleterious mutations.In addition, if some mutations have pleiotropic effects, with beneficial effects in youth, such as high fecundity, but also with a higher subsequent rate of ageing, then they could be incorporated into the population by natural selection, which will act more strongly on the early, beneficial effect.Thus, variation in the rate of ageing would result from the readjustment of a tradeoff between youthful benefits and the subsequent rate of ageing.Both processes imply that faster ageing will evolve where the extrinsic hazard to adults is greatest, a hypothesis in general supported by the data [1,2,17]." + } + ], + "document_id": "0DC57EB6A882DE1734E915DE035D2296", + "engine": "gpt-4", + "first_load": false, + "focus": "api", + "keywords": [ + "genes", + "aging", + "DNA&damage", + "free&radicals", + "telomeres", + "oxidative&stress", + "environmental&factors", + "genetic&factors", + "cellular&repair", + "protein&synthesis" + ], + "metadata": [ + { + "object": "Transient overexpression of WRKY79 in protoplasts results in up-regulation of Gene:542165, Gene:541974, Gene:100274033, Gene:542688, Gene:542150, Gene:542151, Gene:100273457, Gene:100285509, Gene:103626248, Gene:103646045, Gene:100217270, Gene:100279981, Gene:100281950, Gene:542476, Gene:542369, Gene:100281950, and Gene:542260.", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab969966" + }, + { + "object": "Uniform Mu insertion results in up-regulation of cytokinin synthesis genes and down-regulation of cytokinin degradation genes. The protein binds to Gene:103632693, Gene:100502174, Gene:100283866, Gene:542044, and Gene:100037786.", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab983367" + }, + { + "object": "Part of autosomal recessive retinitis pigmentosa gene network established using RetNet info; Part of autosomal recessive cone_cone-rod gene network established using RetNet info; Part of age-related macular degeneration gene network, cone-dystrophy gene network, and retinitis pigmentosa gene network established using GeneNetwork info -ILMN_2829604\\r\\nused by Irene Whitney", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab4267" + }, + { + "object": "TET1 regulates numerous genes defining differentiation programs in the epiblast and extraembryonic ectoderm. In epiblasts, TET1 demethylates gene promoters via hydroxymethylation and maintains telomere stability. It represses a majority of epiblast target genes independent of methylation, partly by regulation of the JMJD8 gene. Dysregulated gene expression in the absence of TET1 causes embryonic defects.", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab769005" + }, + { + "object": "Genome-wide associations P < 5 x 10-8 were found at the PCSK9 gene, the APOB gene, theLPL gene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus.", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab320109" + }, + { + "object": "Genetic risk score GRSNPY analysis found twelve significant P<0.05 serum NPY concentration related SNPs among alpha7 nicotinic acetylcholine receptor gene CHRNA7, insulin receptor gene INSR, leptin receptor gene LEPR, glucocorticoid receptor GR gene NR3C1, and NPY gene. However, after permutation test of gene score the predictive value of GRSNPY remained non-significant P=0.078. CONCLUSIONS: Serum NPY level ...", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab318213" + }, + { + "object": "TYROBP influences a batch of genes that are related to Alzheimer's disease; ZNF329 and RB1 significantly regulate those 'mesenchymal' gene expression signature genes for brain tumors. By merely leveraging gene expression data, Context Based Dependency Network CBDN can efficiently infer the existence of gene-gene interactions as well as their regulatory directions.", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab980273" + }, + { + "object": "Correlation analyses showed that 5hmC enrichment in gene body is positively associated with gene expression level in mouse kidney. Moreover, ischemia reperfusion IR injury-associated genes both up- and down-regulated genes during renal IR injury in mouse kidney exhibit significantly higher 5hmC enrichment in their gene body regions when compared to those un-changed genes.", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab157853" + }, + { + "object": "PI3/PI4-kinase family, and is closely related to ATM, a protein kinase encoded by the gene mutated in ataxia telangiectasia. Shares similarity with S. pombe rad3, a cell cycle checkpoint gene required for cell cycle arrest and DNA damage repair in response to DNA damage. This kinase has been shown to phosphorylate checkpoint kinase CHK1, checkpoint proteins RAD17, and RAD9, as well as tumor suppressor protein BRCA1. Mutations of this gene are associated with Seckel syndrome.", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab4171" + }, + { + "object": "seems that ZnSO4 as a proper antioxidant could improve the aging-related features due to lengthening of the telomeres, increasing the telomerase gene expression, telomerase activity, decreasing aging, and changing the methylation status of hTERT promoter; it could potentially beneficial for enhancing the application of aged-MSCs", + "predicate": "http://www.w3.org/2000/01/rdf-schema#comment", + "subject": "ndd791caee50643ad90a986f563d2a0dab694596" + } + ], + "question": "what causes the aging process", + "subquestions": null, + "task_id": "0DC57EB6A882DE1734E915DE035D2296", + "usage": { + "chatgpt": 8117, + "gpt-4": 4643, + "gpt-4-turbo-preview": 3712 + }, + "user_id": 2 + }, + "document_id": "0DC57EB6A882DE1734E915DE035D2296", + "task_id": "0DC57EB6A882DE1734E915DE035D2296" +} |