Aging – Facts and Theories (Interdisciplinary Topics in gerontology, Vol. 39) (II)
I should probably add a few general remarks related to the previous post before moving on to the coverage of the book. The ‘problem’ is this: I’m getting behind on the book blogging. Earlier this year I had an implicit goal of wanting to cover all non-fiction books I read here. Given that I’ll probably end up reading more than a textbook per week this year and I’ve already gotten significantly behind, I’m no longer sure this goal is achievable in the long run. Currently I’m probably at least something like 6-7 posts behind in terms of stuff I could potentially cover here given what I’ve already read, but I’m not sure how many of those posts I’ll actually ever get to write. You should not make strong assumptions about the quality of the books not covered here based on my decision of whether or not to cover them; sometimes the reason why I’m not blogging a book while reading it (in some sense the preferable approach, because it makes it less likely that I’ll get behind) is simply that it’s a great book which I’d rather be reading than blogging. If a book has a lot of math – like the Ecological Dynamics text, which I’ve still yet to talk about here in part because basically that’s just a math textbook – or is highly technical in other ways, e.g. by dealing with stuff which to a significant extent builds on top of other stuff I’ve read – this book or the endocrinology book are both good examples – then it is really a lot more work to blog the book. The same goes for books which I’ve procured and read offline. Sometimes the relevant decision to make is whether I’d prefer to blog a book or read another book; I spend probably something like 4-5 hours on an Agatha Christie novel, and I can easily end up spending 4 hours on a blog post dealing with a technical book as well.
I think as long as I’m posting something every second day or so on average (I’ve posted 125 posts in 257 days so far this year) I don’t really care too much if I don’t get to cover all the stuff I read, even if I’d prefer to cover it all.
Okay, back to the book. As mentioned in the first post, I gave it one star, but that doesn’t mean there isn’t some interesting stuff in there. There are a lot of these things around: ‘[…]’ in my coverage below, and they’re there for a reason. To be frank, if they weren’t there the quotes from the book would be as unreadable as the book is, and I don’t want that kind of stuff on my blog. The language in many chapters of this book is simply terrible, and I’ve tried to make it less terrible by quoting very selectively and very strategically. If you want to make sure I’m not misrepresenting the views of the authors through the ‘active quoting strategies’ I employ below you’re very welcome to read the book yourself and compare my quotes with the original coverage – I’d consider it likely that you’d prefer my coverage to theirs if you were to do that.
“The cross-linking theory [of aging assumes] that aging is due to the formation of intra- and/or intermolecular covalent cross-links altering the basic structure of the macromolecules to such an extent that even their functions become compromised. […] age-dependent increase in […] cross-linking is fully supported by […] heat denaturation experiments [16–20] […] The main conclusion [from these] was that many of the H-bonds are transformed into covalent cross-links in collagen during aging [and collagen is really important as: “the largest fraction of proteins in the body is the collagen[,] amounting to about 33% of the total protein content”].”
“[T]he free radical theory of aging (FRTA) […] assumes that oxygen free radicals are harmful byproducts of the aerobic life, and as such, are responsible for aging and numerous diseases. Since most of the oxygen free radicals are strong electron acceptors, their main effect is the formation of cross-links, i.e. they may well be the causes of the age-dependent cross-linking of proteins. […] free radical-induced cross-linking is strongly density dependent, i.e. the increased physical density of any biological structure will enhance the cross-linking efficiency of the radical-generating systems. […] this phenomenon has a great significance in the age-dependent alterations of the most compact biological structures, like the cell membranes .”
“[A] new […] interpretation of the possible biological role of oxygen free radicals in the living state, cell differentiation and aging […] has been called the membrane hypothesis of aging (MHA) […] The MHA attributes a leading role in differentiation and aging processes to the plasma membrane, undergoing inevitable, continuous alterations during […] life […]. The MHA considers as the main damaging factors of the plasma membrane of cells the following two processes. (a) The continuous production of OH− free radicals […] In this sense, MHA follows the concepts of the FRTA. This is justified on the one hand by the widely proven damaging effects of these free radicals on practically [every] class of the biological macromolecules. It is a fact, on the other hand, that the author of MHA has also demonstrated that the oxyradicals cannot be considered only as damaging factors, since their formation is an essential attribute of the living state [39, 40, 45]. Nevertheless, from the point of view of experimental gerontology, the damaging effect of these radicals remains anyway of essential importance. Analyses of the quantitative aspects of the free radical-induced molecular damage have revealed that the cell plasma membrane is the weakest point of the cellular structure […] plasma membranes are really the most critically sensitive structures in […] living cells. (b) In addition to the free radical-induced damage, the cell plasma membrane is exposed to another damaging factor called residual heat production , which is negligible or absent in other intracellular membranous components, like the mitochondrial or the endoplasmic reticulum membranes. […] Because the polarity of the cell membranes is discharged very quickly (in about 1–2 ms during each action potential), and also rather frequently (in certain neurons up to 50–100 times per second), the cell membrane is exposed all the time to a considerable local heating. Due to the extremely short time of its development, about 10% of the initial heat cannot be dissipated by the environment, called residual heat remaining in the membrane . As a consequence of this, in spite of the fully recovered membrane potential, one has to assume some persisting alterations of the membrane structure after each action potential. This fact is of great importance; however, most of the experimental gerontologists are not even aware of it. […] This type of membrane alterations can be considered as true ‘wear and tear’ phenomena which certainly contribute to the velocity of the plasma membrane deterioration.”
“[A]ge-dependent water loss starts practically during the embryonic development of mammals, i.e. it is an intrinsic part of the developmental and maturation processes. The whole ontogenesis can be considered as a procedure during which the highly hydrated state of embryos (90–92% water at the beginning), in newborns and young individuals is gradually transformed into a more and more dehydrated one (40–50% water in old body). It is obviously necessary to reach a sufficient increase in the dry mass content in all tissues, organs, etc. in order to achieve a sufficient physical strength of the body to support the load, to perform the requested work, etc. Therefore, this process is useful and absolutely necessary. However, because of the ever ongoing character of this process, it becomes rate limiting first for further growth, and self-destroying during the later phases of life. These considerations imply that the driving ‘force’ of both maturation and aging is the same, i.e. there is no special aging process, just the dehydration of the body beyond the optimum maturation state [causing] a progressive, destructive, inherent and universal rate limitation for […] physiological performance”
“The oncogenes were discovered first in tumor tissues during the early 1980s, and were thought to be of viral origin, but were found very soon in all eukaryotes from yeast to human cells. They have various viral (v-) and cellular (c-) families, the number of which is above 40. The c-oncogenes are also termed proto-oncogenes; they code for proteins being strictly involved in mitotic regulation. Nowadays, they are regarded as playing vital roles in the normal control of mitosis and cell differentiation depending upon cell types and the actual state of maturation. In addition to the oncogenes, so-called antioncogenes (or oncosuppressor genes) have also been identified. These are genes the products of which are important in suppression of cell division and causing differentiation, senescence or apoptosis of cells. […] from the point of view of the MHA, it seems to be extremely important that many of the products of the so far explored oncogenes and antioncogenes are localized in the cell plasma membrane.”
“[The] strong conflict between AMA and A4M [the American Academy of Anti-Aging Medicine] prompted me as the Editor-in-Chief of the journal Archives of Gerontology and Geriatrics to write an Editorial  proposing a consensus, according to which aging should generally be considered as a natural AGHD [Adult Growth Hormone Deficiency] syndrome treatable by hrGH [recombinant human GH].”
I included the quote in the paragraph above for one reason only: To remind people reading along that I don’t always trust the judgment of the authors I read, and that I’m sometimes quite skeptical about what they have to say. Here’s another view on that matter: “There’s little evidence to suggest human growth hormone can help otherwise healthy adults regain youth and vitality. In fact, experts recommend against using HGH to treat aging or age-related conditions.” (link). I don’t take people like ‘the mayo clinic staff’ to be undisputed authorities which I should never question either – people in similar positions have taken medical decisions which I consider to be questionable before, as a specific example I might refer to the comments I made while reading Kolonin et al. about the website of Johns Hopkins University and its coverage of reconstructive breast surgery (see this link). But the situation here is different, as the mayo guys obviously aren’t the ones who have a lot of explaining and justification to do here. I think the author of that chapter would find it very hard to obtain consensus even among the contributors to the publication in question, as more than one of them have in their coverage made clear that they think he’s wrong (not directly, but certainly indirectly).
“Aging is a complex process of progressive decline in overall physiological functions, resulting in a diminished capacity to withstand internal and external damage and an increased susceptibility to diseases and risk of death. The process of aging is controlled by many factors including genetic and environmental influences, and many theories have been proposed to explain the phenomenon of aging. Recent studies have implicated mitochondrial dysfunction and oxidative stress in the aging process and in the pathogenesis of age-associated diseases. It is hypothesized that damage to mitochondria including mitochondrial DNA (mtDNA) caused by the production of reactive oxygen species (ROS) during cellular respiration is one of the drivers of aging. These theories (the free radical theory and the mitochondrial vicious cycle theory of aging) provide an important conceptual framework and have led to interventions aimed at decreasing the level of ROS for health benefits. However, there is an increasing body of evidence challenging these theories, which has led to the emergence of new hypotheses on how age-associated mitochondrial dysfunction may lead to aging”
“ROS are produced as by-products of aerobic metabolism in cells, and mitochondria are the major sites of ROS generation. In humans, more than 90% of oxygen is consumed by mitochondria, and 1–5% of the consumed oxygen is transformed into superoxide because of electron leakage of the electron transport chain (ETC). Superoxide generated in mitochondria is then converted to hydrogen peroxide […] Depending on their types and cellular levels, ROS can act as either crucial biological or deleterious agents. […] under pathophysiological conditions, overproduction of ROS can interact with DNA, RNA, lipids and proteins, leading to destruction or irreversible alteration of the functions of the targeted molecules. Consequently, ROS are identified as major contributors of cellular damage. ROS-induced DNA damage […] can result in alterations in transcription and signal transduction, replication errors, and genomic instability […] Accumulation of ROS and oxidative damage is one of the cellular hallmarks of aging. […] In addition to being a main source of ROS, mitochondria are the prime targets of oxidative damage, which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. As an extension of the free radical theory, the mitochondrial vicious cycle theory of aging emphasizes and refines the central role of mitochondria in the aging process. […] A wide spectrum of alterations in mtDNA including point mutations, deletions and duplications have been found to accumulate in a variety of tissues during aging . The accumulation of oxidative stress-induced mtDNA mutations has been shown to correlate with a progressive decline in mitochondrial function and contribute to age-related physiological decline [38, 55]. In addition to its proximity to the source of oxidants, mtDNA lacks protection by histones and the DNA repair capacity in mitochondria is relatively low . Moreover, the mitochondrial genome lacks noncoding introns, which increases the likelihood of damage to a coding region and consequently affects the integrity of encoded RNA and proteins. These characteristics make mtDNA more vulnerable to oxidative damage than nuclear DNA in mammalian cells . More importantly, damage to mtDNA can be propagated as mitochondria and cells divide, leading to the amplification of the physiological consequences of the damage.”
“A large body of evidence suggests a link between aging and increased ROS production, accumulated oxidative damages and declined mitochondrial function. Whether and how these changes contribute to aging is an area of interest in aging research. […] considerable progress has been made in our understanding of the role of oxidative stress and mitochondrial dysfunction in aging and age-associated diseases. However, a number of recent studies have challenged the free radical and mitochondrial theories of aging, which postulate a detrimental and toxic role of ROS and dysfunctional mitochondria in aging. Some disconnections exist between oxidative stress and longevity. Long-lived naked mole rats are found to have higher levels of oxidative damage than the short-lived mice . Caloric/glucose restriction extends life span in yeast and Caenorhabditis elegans, but induces mitochondrial respiration and increases oxidative stress [256–259]. Overexpression of major antioxidant enzymes including Cu/ZnSOD, catalase, or combinations of either Cu/ZnSOD and catalase or Cu/ZnSOD and MnSOD does not extend life span in mice . Furthermore, studies have found that mtDNA mutations are generated mainly by replication errors rather than by accumulated oxidative damage . […] 261] . Collectively, these findings suggest that ROS production and mitochondrial dysfunction are not the universal cause of aging in all species. ROS have recently emerged as signaling molecules which facilitate adaptation to stress and maintain cellular homeostasis . The gradual ROS response theory of aging postulates that ROS are not the cause of aging, but rather represent a stress signal in response to age-dependent damage . This theory suggests that ROS can be beneficial by serving as molecular signals to stimulate endogenous defense mechanisms and promote stress resistance and longevity, although high levels of ROS have a deleterious role in aging and late-onset diseases. There is increasing evidence indicating that mitochondrial ROS can induce beneficial responses to cellular stresses during aging.”
“We insisted in the previous sections of this chapter on the crucial role of cell-matrix interactions for correct tissue and organ function. These interactions are mediated by receptors, integrins, the elastin receptor and several others. Messages delivered to cells by these receptors, originating from the ECM [extracellular matrix] are then further transmitted and targeted to intracellular and intranuclear organelles where the message has to be interpreted […] Cells can also send messages to constituents of the surrounding matrix to modify its intermolecular interactions and functions. […] Besides […] direct cell-matrix communication, a number of other messages can and do reach the cells to modulate their behavior. Such messages, as for instance hormones, cytokines, growth factors and many others, communicate with the cells by receptors on the cell membrane, intracellular and intranuclear. […] several receptor-mediated functions decline with age because [of] either […] the loss of receptors or their uncoupling from their specific signalling pathways. […] one of the hallmarks of aging is the decline of a number of physiological functions in response to a variety of stimuli. Among these are the best known and most studied endocrine functions underlying menopause and andropause. Another group of vital physiological functions concern the regulation of cardiovascular functions, intensely studied over decades by a number of investigators […] A third field of intense investigations concerns the nervous system […] Most of these functions are regulated by receptor ligand interactions, followed by the transmission of the message conveyed by the ligand, a hormone for instance, to the interior of the cell where it has to elicit the reaction specified by the nature of the ligand. A complicating factor for such studies is the fact that most receptor-mediated processes proceed by a series of successive steps, all mediated by ‘second messengers’ or other comparable intermediary reactions before reaching the target of the message […] This stepwise transmission of the specific message between the receptor and the corresponding cell machinery complicates the task for the elucidation of the precise mechanism of the age-dependent loss of function.”
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I am a student of economics from Denmark.
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