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Is Programmed Aging a Cause for Optimism?
Abstract
Aging is now viewed as programmed under genetic control by a growing minority of evolutionary biologists, and a larger proportion of researchers in gerontology. The hypothesis of programmed aging has been regarded as encouraging for anti-aging science. Some mechanisms of programmed aging may present ready targets for medical interference [mitigation alleviation attenuation], while other kinds of programmed mechanism may yet prove to be refractory. The most promising possibility is that the machinery responsible for maintenance of the vibrant and youthful state of the body is never really lost, but de-commissioned by hormonal signals in the aging body; restoring a youthful signaling environment should then be sufficient to prompt the body to restore itself. But it is also possible that aging may be programmed in a way that does not facilitate anti-aging interventions. We identify two possible cases: In the first, the body is programmed to age via neglect rather than by affirmative self-destruction, so that damage is accumulating that the body is beyond the body's power to repair. In the second, aging is controlled by an epigenetic clock whose workings are so intricate as to be intractable for human mastery in the foreseeable future. There is substantial evidence that first of these is not a likely scenario, but the jury is still out on the second.
... The epigenetic age of a cell or tissue is reflected by the level of methylation of discrete CpG sites that constitute an "epigenetic clock" (Horvath, 2013;Stubbs et al., 2017). This epigenetic clock is considered as a biomarker of aging (Christiansen et al., 2016;Levine et al., 2015) and may even be part of a programmed cellular aging process (Mitteldorf, 2015). The epigenetic clock is based on DNA methylation and does not include the status of histone marks. ...
Complex biological processes, such as organogenesis and homeostasis, are stringently regulated by genetic programs that are fine-tuned by epigenetic factors to establish cell fates and/or to respond to the microenvironment. Gene regulatory networks that guide cell differentiation and function are modulated and stabilized by modifications to DNA, RNA and proteins. In this review, we focus on two key epigenetic changes - DNA methylation and histone modifications - and discuss their contribution to retinal development, aging and disease, especially in the context of age-related macular degeneration (AMD) and diabetic retinopathy. We highlight less-studied roles of DNA methylation and provide the RNA expression profiles of epigenetic enzymes in human and mouse retina in comparison to other tissues. We also review computational tools and emergent technologies to profile, analyze and integrate epigenetic information. We suggest implementation of editing tools and single-cell technologies to trace and perturb the epigenome for delineating its role in transcriptional regulation. Finally, we present our thoughts on exciting avenues for exploring epigenome in retinal metabolism, disease modeling, and regeneration.
... 70 Moreover, it has been proposed that the functional decline of aged brain may be due, at least in part, to decreased trophic support, changes in synaptic efficacy, and an increase in ROS production in astrocytes. 71,72 In agreement with this hypothesis, more recent in vitro studies demonstrated that hypothalamic astrocytes from aged Wistar rats are able to remodel and change their neurochemical properties compared to newborn and adult rats. 73 Age-related variations were observed in the regulation of glutamatergic homeostasis (with a significant reduction of glutamate production in aged astrocytes), glutathione biosynthesis, amino acid profile, and glucose metabolism. ...
... During aging, alterations in intracellular signaling pathways, such as activation of nuclear factor kappa B (NFκB), promote inflammatory responses [23,24]. Moreover, decreased trophic support, changes in synaptic efficacy, and increase in reactive oxygen species production may be involved in the functional decline of the aging brain [25][26][27]. ...
The hypothalamus is a crucial integrative center in the central nervous system, responsible for the regulation of homeostatic activities, including systemic energy balance. Increasing evidence has highlighted a critical role of astrocytes in orchestrating hypothalamic functions; they participate in the modulation of synaptic transmission, metabolic and trophic support to neurons, immune defense, and nutrient sensing. In this context, disturbance of systemic energy homeostasis, which is a common feature of obesity and the aging process, involves inflammatory responses. This may be related to dysfunction of hypothalamic astrocytes. In this regard, the aim of this study was to evaluate the neurochemical properties of hypothalamic astrocyte cultures from newborn, adult, and aged Wistar rats. Age-dependent changes in the regulation of glutamatergic homeostasis, glutathione biosynthesis, amino acid profile, glucose metabolism, trophic support, and inflammatory response were observed. Additionally, signaling pathways including nuclear factor erythroid-derived 2-like 2/heme oxygenase-1 p38 mitogen-activated protein kinase, nuclear factor kappa B, phosphatidylinositide 3-kinase/Akt, and leptin receptor expression may represent putative mechanisms associated with the cellular alterations. In summary, our findings indicate that as age increases, hypothalamic astrocytes remodel and exhibit changes in their neurochemical properties. This process may play a role in the onset and/or progression of metabolic disorders.
... Now, the manner in which anti-aging discourse employs molecular level processes is suggesting that they can be directly made to immortalize the organism. For example, if we look at the hopes rested upon telomeres and telomerase in promoting prolongevity and health (Mitteldorff, 2015;Varela et al., 2016), we are immediately faced with the problem of what do telomeres actually achieve for an organism? In addition, laboratory research is, of course, not at first applied to humans and so there is also the question of species-specific effects: what would telomeres, lengthened in mice -who 'are not among the species whose lifespans are limited by telomere attrition' (Mitteldorf, 2013: 1056) -manifest in human beings? ...
Biosemiotics and the analysis of biopower have not yet been explicitly brought together. This article attempts to find their connecting points from the perspective of biosemiotics. It uses the biosemiotic understanding of the different types of semi-osis in order to approach the practices of biopower and biopolitics. The central concept of the paper is that of the 'semiotic threshold'. We can speak of (1) the lower semiotic threshold, signifying the dividing line between non-semiosis and semi-osis; and (2) the secondary semiotic thresholds, signifying the borders between different types (iconic, indexical, symbolic) of semiosis. Speaking in terms of types of semiosis means speaking in terms of different capabilities for normativity, which is why the article uses the approaches of Michel Foucault on normalization in biopower and of Georges Canguilhem on organismic normativity. As an example on which biopolitics and biosemiotics could connect, the discourse of regenerative and anti-aging medicine is used.
... Aging is a natural process that induces numerous changes in the brain functionality, including alterations in synaptic efficacy, changes in neuron-glia communication with consequent impairment in cerebral activities, and increases in reactive oxygen species (ROS) and inflammatory mediators [20][21][22]. Understanding and managing these alterations may be an important strategy to extend a healthy life span. As such, the association among oxidative stress, inflammation, and aging is based on complex molecular and cellular changes that have only just begun to be understood. ...
Guanosine, a guanine-based purine, has been shown to exert beneficial roles in in vitro and in vivo injury models of neural cells. Guanosine is released from astrocytes and modulates important astroglial functions, including glutamatergic metabolism, antioxidant, and anti-inflammatory activities. Astrocytes are crucial for regulating the neurotransmitter system and synaptic information processes, ionic homeostasis, energy metabolism, antioxidant defenses, and the inflammatory response. Aging is a natural process that induces numerous changes in the astrocyte functionality. Thus, the search for molecules able to reduce the glial dysfunction associated with aging may represent an approach for avoiding the onset of age-related neurological diseases. Hence, the aim of this study was to evaluate the anti-aging effects of guanosine, using primary astrocyte cultures from newborn, adult, and aged Wistar rats. Concomitantly, we evaluated the role of heme oxygenase 1 (HO-1) in guanosine-mediated glioprotection. We observed age-dependent changes in glutamate uptake, glutamine synthetase (GS) activity, the glutathione (GSH) system, pro-inflammatory cytokine (tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β)) release, and the transcriptional activity of nuclear factor kB (NFkB), which were prevented by guanosine in an HO-1-dependent manner. Our findings suggest guanosine to be a promising therapeutic agent able to provide glioprotection during the aging process. Thus, this study contributes to the understanding of the cellular and molecular mechanisms of guanosine in the aging process.
Cellular senescence, which is associated with aging, is a process by which cells enter a state of permanent cell cycle arrest, therefore constituting a potent tumor suppressive mechanism. Recent studies show that, despite the beneficial effects of cellular senescence, senescent cells can also exert harmful effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescent-associated secretory phenotype (SASP), which entails a striking increase in the secretion of pro-inflammatory cytokines. Here, we summarize our knowledge of the SASP and the impact it has on tissue microenvironments and ability to stimulate tumor progression.
Natural selection acts primarily on organisms, and the existence of evolved, active, internal mechanisms that cause organismal death would seem paradoxical. However, there is substantial evidence that internal death promoting mechanisms exist and are taxonomically widespread. Where these are argued to be 'programmed organismal death' (POD), they require evolutionary explanations. Any such explanation must draw on our understanding of fitness trade-offs and multiple levels of selection in evolution. This review includes two main categories of putative POD: senescence in multicellular-organisms, and programmed cell death in unicellular organisms. The evidence for POD as a genetically controlled phenotype is strong for semelparous and significant but more controversial for iteroparous plants and animals. In multicellular organisms the program frequently (although not always) appears to be the result of fitness trade-offs. Here the death phenotype itself is not adaptive but the fitness related program most likely is. However, in some cases of behavioral suicide, particularly in insects, there are distinct advantages to kin and group level benefits may play a role. In unicells, programmed death is ubiquitous and POD often provides benefits to others. While benefits do not equate with adaptations, they are consistent with it. Here, death may be adaptive at a level other than the individual cell. In other instances of POD in unicells the phenotype (eg autophagy) can be explained as pleiotropy. The overall picture of POD as a natural phenomenon is still emerging, and continued work on diverse lines of evidence is necessary to complete our evolutionary understanding of this apparent paradox. While some questions remain, we conclude that POD is most likely, in some circumstances at least, adaptive.
Yeast deprived of nutrients exhibit a marked life span extension that requires the activity of the NAD+-dependent histone deacetylase, Sir2p. Here we show that increased dosage of NPT1, encoding a nicotinate phosphoribosyltransferase critical for the NAD+ salvage pathway, increases Sir2-dependent silencing, stabilizes the rDNA locus, and extends yeast replicative life span by up to 60%. Both NPT1 and SIR2provide resistance against heat shock, demonstrating that these genes act in a more general manner to promote cell survival. We show that Npt1 and a previously uncharacterized salvage pathway enzyme, Nma2, are both concentrated in the nucleus, indicating that a significant amount of NAD+ is regenerated in this organelle. Additional copies of the salvage pathway genes, PNC1, NMA1, andNMA2, increase telomeric and rDNA silencing, implying that multiple steps affect the rate of the pathway. AlthoughSIR2-dependent processes are enhanced by additional NPT1, steady-state NAD+ levels and NAD+/NADH ratios remain unaltered. This finding suggests that yeast life span extension may be facilitated by an increase in the availability of NAD+ to Sir2, although not through a simple increase in steady-state levels. We propose a model in which increased flux through the NAD+ salvage pathway is responsible for the Sir2-dependent extension of life span.
Aging is a major concern in developing societies, which are characterized by an escalation in the aged population as well as in the prevalence of many chronic diseases associated with this inevitable biological process. There is a strong desire to delay aging and increase the length of disease-free life. For that purpose there is a need to better understand the human aging process, as the mechanisms that regulate aging remain largely unknown. The adult stem cell reservoir, which not only declines in size with age, but also particularly handicaps those regenerative tissues repopulated by this reservoir of stem cells, deserves special consideration. We have recently reported the characterization of a new stem cell human experimental model, based on posttranslational defects of the LMNA gene expression associated with progeroid syndromes. In this work, we summarize the necessity of developing reliable human experimental models for the study of human stem cell aging, and outline the phenotypes exhibited by this new experimental human aging model due to accumulation of an aberrant LMNA product with detrimental repercussions to in vivo functionality. This in vitro model has been fundamental for the identification of a novel role of a known transcription factor in human stem cell aging, demonstrating the potential of the model as a tool to unravel the molecular mechanisms governing human aging.
The effect of predation by the aquatic dipteran larva Chaoborus americanus on genetic diversity and life-history evolution in the cladoceran Daphnia pulex was investigated in large replicate laboratory populations. Instantaneous daily loss rates of clonal diversity and genetic variance for fitness indicate that 93-99% of initial genetic diversity can be removed from populations during the 8-12 generations of clonal reproduction that occur each year in natural populations. In the absence of predation, the principal evolved changes in mean population life history were smaller immature body size and increased and earlier fecundity. In the presence of size-selective Chaoborus predation, populations evolved toward larger body size and increased and earlier reproduction. The difference between these two trajectories is an estimate of the direct additive effect of Chaoborus predation. This effect was manifested as evolution toward larger body size with a trend toward earlier and increased reproduction.
DNA damage can lead not only to mutations and chromosome abnormalities, but also to epigenetic effects on gene expression. It is therefore very important to consider the possible effects of oxidative damage to DNA on epigenetic controls. In somatic cells of higher organisms there are two heritable systems which exist side by side (Holliday, 1990). Classical genetics is concerned with the inheritance of differences in DNA sequences. These differences are transmitted through mitosis and meiosis and can only be reversed or changed by rare mutations. Epigenetics is the study of the changes in gene activity during development. The epigenetic basis for gene expression can be stably inherited through mitosis, since specialised differentiated cells which divide maintain their phenotype. However, there can also be instability, since stem line cells can divide both to form cells which will later differentiate, and also cells which retain their stem cell function. Whereas classical genetic inheritance is concerned with individual cell lineages, epigenetic changes during development commonly occur in groups of cells sometimes called “polyclones” (Crick and Lawrence, 1975). Such changes may be strongly influenced by external effectors (morphogens, hormones, growth factors, or other diffusible agents), whereas the genetic information embodied in DNA sequences is not changed by external influences. Epigenetic changes are commonly reversed in each generation, for example, the inactive X chromosome in female mammals is reactivated before the gametes are produced. The process of genomic imprinting depends on the addition of information to DNA which is different in male and female gametes. Imprinting can also be regarded as an epigenetic mechanism, which can be reversed in each generation.
Nature 464, 504–512 (2010) In this review, the first line of the Figure 2 legend inadvertently states that the arrows depict changes in gene expression. The correct statement is that the arrows depict changes in gene-product activity. In the section entitled ‘Inhibition of respiration’, the second sentence inadvertently states that perhaps increasing respiration extends lifespan for one reason and inhibits it for another.
In the 60 years since Medawar questioned the assumption that aging is a selected trait with a fitness benefit, mainstream biogerontology has overwhelmingly adopted the view that aging is a product of evolutionary neglect rather than evolutionary intent. Recently, however, this question has come to merit further scrutiny, for three reasons: a variety of new ways in which aging could indeed be “programmed” have been proposed, several phenomena with superficial similarities to programmed aging have been suggested to offer evidence for it and against the mainstream consensus, and above all it has become appreciated that the existence or otherwise of “pro-aging genes” has enormous implications for determining our optimal strategy for the medical postponement of age-related ill-health. Accordingly, it is timely to revisit the arguments and data on this topic. In this article I discuss difficulties in reconciling the programmed-aging concept with existing data, flaws in various arguments given by others that existing data prove aging to be programmed, and extensions of these considerations to various phenomena that in one or another way resemble programmed aging. I conclude that, however much we might wish that aging were programmed and thus that the ill-health of old age could be greatly postponed just by disabling some aspect of our genetic makeup, the unfortunate truth is that no such program exists, and thus that our only option for substantial extension of healthspan is a divide-and-conquer panel of interventions to repair the damage that the body inflicts upon itself throughout life as side-effects of its normal operation. I explicitly avoid arguments that rely on unnecessarily abstruse evolutionary theory, in order to render my line of reasoning accessible to the broadest possible audience.