Aging – Facts and Theories (Interdisciplinary Topics in gerontology, Vol. 39) (I)

I said some not particularly nice things about this book in my goodreads review. While writing this post I was actually starting to seriously question my rating and asking myself whether I should make some adjustments to the review as well. Given the amount of blogging-worthy stuff included in the first part of the book, in combination with the fact that I’ve still yet to cover a couple of chapters I liked, I thought it might be unfair of me to give this publication one star, all things considered. But I’m not sure if I’ll change my rating. This part of my review stands: “if I don’t give this publication one star it’s really hard for me to imagine when I’d ever do that in the context of an academic publication.” The baseline requirements are set at a high level when you’re dealing with publications like these, and the rating should reflect that.

Below I have added some stuff from the first chapters of the book, and a few comments of my own.

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“There is now strong evidence that telomere length is reduced during the serial subculture of human fibroblasts [11–13]. At some point before or during the formation of these cells, the enzyme telomerase, which maintains telomere length, is lost. It has therefore been suggested that commitment is in fact the loss of telomerase [14]. From this point, the cells can divide a given number of times, until the loss of DNA from the ends of chromosomes results in the cessation of cell division. The commitment theory proposes that this number of divisions, the parameter M, is constant, or close to constant.”

I believe some aspects of this line of work is well known also by people not working in the field, though I may be mistaken; I assume many people curious about these things have heard about stuff like the Hayflick limit. The book has quite a bit of stuff on research dealing with these things, and below are some critical remarks from the book on this topic:

[Works on human fibroplasts has] led to the concept that the hallmark of cellular aging is the postmitotic cell, the so called senescent cell, which would be one of the causes of the organism’s aging. However, there is no evidence showing that the human organism ages because somatic cells lose the potential to divide. In fact, the assumption goes against all the experiments that have tested the capacity of fibroblasts obtained from old donors to divide. It is obvious that in old age our cells are still capable of proliferating; what takes place is a deregulation in the proliferative response rather than the absence of the capacity to divide [14]. […] Unfortunately, the term cell senescence [has been] generalized and now encompasses anytime a cell enters an irreversible growth arrest due to a variety of causes. Sometimes quite harsh treatments [have been] used to induce growth arrest [in research], which not surprisingly [have induced] DNA damage and arrest of cell division. Since some investigators believe that the terminal postmitotic stage of proliferating cell populations is originated by oxidative stress, hydrogen peroxide is one of those molecules used to induce the ‘senescent phenotype’ […] [A problem is] that in the absence of detailed molecular data on what constitutes normal aging, it is difficult to decide whether the changes [which have been] reported reflect mechanisms underlying normal cellular aging/senescence or rather produce a mimic of cellular aging/senescence by quite different pathways. […] Now that the term cell senescence is well established to designate a postmitotic state, it is difficult to change the usage; however, it should be used only operationally without any connection with aging of the organism.”

“One modification [of DNA methylation during replicative aging] has particularly drawn the attention of gerontologists; it concerned the shortening of chromosome ends, the telomeres. One can still see claims in the literature that this is one of the main causes of aging. […] Since some immortal cell lines express the enzyme telomerase and develop the capacity to reconstitute telomeres after replication, the link between telomere integrity and replication potential seemed established; investigators were quick to equate telomere shortening with proliferation and aging. The reasoning was based on the syllogism: the number of potential divisions decreases with aging, telomeres are shortened during cell proliferation, hence aging is a function of telomere shortening. The syllogism is unjustified because the major and minor propositions have not been ascertained in comparative gerontology studies.
The erosion of telomeres through division is not universal. In humans, the division in vitro of normal keratinocytes [53, 54] , cardiomyocites [55] and astrocytes [56] is independent of telomere size. Results obtained with normal in vivo and in vitro lymphocytes vary with the laboratory and the methodology. […] In humans, telomere lengths [in one study] did not show a clear correlation with tissue renewal times in vivo […]; moreover, the rate of telomere loss slows throughout the human life span [63]. Fibroblasts from patients with Werner’s syndrome, which have a shorter life span than those of normal age-matched control donors, do not have shorter telomeres than control cells [64]. […] There are other caveats concerning the relationship between telomere shortening and proliferation. Human fibroblasts maintained in the presence of 3% oxygen instead of the usual concentration of 20% have an increased proliferation potential but have shorter telomeres [23]. Radiation-induced senescence-like growth arrest is independent of telomere shortening [68]. […] Telomere biology seems to vary with the species in a way unrelated with aging and with the respective cell proliferation life span in vitro. In non-human primates such as rhesus monkey, Japanese monkey, crab-eating monkey, chimpanzee, and orangutan, TRF [Terminal Restriction Fragment] length was more than double that of human somatic tissues [69]. […] Hamster embryonic fibroblasts express telomerase throughout their replicative life span and the average telomere length does not decrease [73]. Long telomeres, fast cell replicative aging in vitro and short longevity are found in either wild or inbred laboratory mice. […] In summary, it seems that the regulation of the length of telomeres has no implications for aging.”

Note that one needs to be careful about which conclusions to draw here. Hayflick’s finding seems to be correct:

“Most scientists who worked according to the guidelines published by Hayflick could reproduce his results. During the 2nd part of the last century, cell and tissue culture methods became standardized, and culture dishes and media became commercially available. This largely contributed to the interlaboratory standardization of culture methodology and settled to a large extent the controversies. Hayflick’s paradigm, stating that normal nontransformed cells cannot duplicate indefinitely in culture unless transformed into malignant cells, is now largely accepted.”

And I think the point is not that Hayflick’s finding was wrong, but rather that the relevance of this finding to how organisms actually age has been called into question. There’s probably a theoretical limit, but the limit is not particularly relevant to the way organisms age because organisms die before such considerations ever become relevant – this was my reading of what some of the authors thought about these things. Whether or not I’ve misunderstood the authors, at least this seems like a sensible solution to me to the problem of how to interpret the many different findings in this field.

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Below I have added some coverage from a chapter on ideas about aging derived from evolutionary biology – again I assume some of these ideas may already be familiar to people reading along because such ideas are not exactly unknown, but that perhaps there’s even so perhaps some new stuff included in that part of the coverage as well:

“for any species, there is a compromise between longevity and the other life history traits. Some species, like elephants, need to live long to thrive or simply survive while for other ones, like mice, a high lifespan is superfluous. […] any theory of aging needs to take into account that longevity, like the other life history traits, does not evolve freely, and any hypothesis positing that longevity of human beings could reach astronomic values simply ignores basic concepts in biology.”

“For most of species, life in the wild is rather short because of the threats encountered by animals, with the consequence that many of them die at a younger age than they would in a protected environment. The basic consequence is that all events occurring beyond some age are of no importance to the species and to most of animals […] in animals, deleterious mutations expressed at young age are selected against, because they impair reproduction. […] By contrast, if the mutations are expressed at old age only, they will not be selected against because their bearers have already transmitted their genes to the next generation […] Mutations only expressed at old age will have no real effect on animals because most of them are already dead at this age […]. If the whole process is repeated for many mutations and generations, one can easily understand that deleterious mutations will accumulate at old age, i.e. animals will be loaded with many health problems if they reach old age. This theory [is] called the theory of the accumulation of mutations at old age […] Williams [added to this theory the idea that] some alleles could have favorable effects at young age and deleterious ones at old age […] [the idea being that such] alleles could be selected due to their positive effects at young age, despite the negative effects at old age. […] Williams’ theory is […] called the antagonistic pleiotropy theory of aging. […] for the time being, the evidence in favor of the hypothesis of the antagonistic pleiotropy theory of aging appears to be limited. In addition, because only a very few genes have been found to be associated with aging or longevity, it is difficult to show that mutations accumulate with age, as postulated by the theory of the accumulation of mutations at old age. However, it would be going too far to claim that genes with negative effects at old age (and possibly positive effects at young age) do not exist. For instance, a high growth hormone level is a risk for premature mortality in middle-aged men [50], while a too low level at young age impairs growth. This increased growth hormone level is probably not linked to a severe mutation in a single gene”

“The third classic evolutionary theory of aging, not contradictory with the two previous ones [mentioned in the paragraph above], is the disposable soma theory championed by Kirkwood [23] who argued that the germ line is immortal but soma is disposable, hence the name of the theory. This author emphasized that, because life is short in the wild, it is useless to invest more energy in body maintenance mechanisms (immunity, cellular repair processes, and so on) than needed to provide the expected lifespan in the wild, and thus soma is disposable. Investing more would be a waste and this energy would be better used in reproduction. […] it would be very dogmatic to consider that the whole aging process could be explained by relying on these theories, and the mainstream idea is that some parts of the aging process can be explained by these theories, but that they cannot explain all features of aging.”

“According to the previously described theories, aging is the result of either the accumulation of mutations at old age [21] , negative effects at old age of alleles with positive effects at young age [22], or a compromise between maintenance processes and reproduction [23]. Thus, they have a common theoretical background: genes do not program aging as they program development. Aging occurs because there is an age beyond which the probability to survive in the wild is very low. Beyond this age, no maintenance process can be selected during the course of evolution, simply because most of animals living in the wild are already dead. As no maintenance process has been selected, it is inevitable that the organism will be more and more unable to resist the various threats (e.g. diseases, molecular damage) and to remain as efficient as it was at young age (cognition, physical ability, and so on), and this aging process will be observed if animals live in protected environments. Therefore, it is unneeded to make the hypothesis that genes actively promote aging, simply because aging, contrary to development, can occur without the existence of such genes. If we would nevertheless accept that such genes do exist, it would imply that, as for all the other genes, mutants would also exist: some animals could escape the ‘aging program’ and these ever young animals would be potentially immortal. These mutants would thus only die of external causes, such as accidents, and could reproduce when the other animals are already dead. Due to this selective advantage, these mutants would become very common in a few generations and most of animals would be potentially immortal: such mutants have never been observed […] Aging is not due to genes actively programming aging but […] to the deleterious effects at old age of some genes that have not been selected to display these effects […] If aging is not programmed by genes, the basic consequence is that claims that studies of nematode mutants with extended longevity could allow ‘to think ageing as a disease that can be cured, or at least postponed’ [26] are not warranted. These mutants live longer because for this species increasing longevity is an appropriate strategy when food is scarce […], but it is an illusion to think that a gene governing aging has been discovered […], and there is no reason to be ‘so excited about the prospect of searching for – and finding – the causes of ageing and maybe even the fountain of youth itself’ [26].”

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One more observation which although unrelated to the above coverage seemed to me relevant to include in this post as well:

“A remodeling at the cellular level resulting from a different equilibrium between cell compartments, the decline of one leading to overexpression of another, […] contributes to the aging syndrome […] In the skin [for example], the loss of elasticity and increased wrinkling are the result of the rearrangements in the relative proportion of the molecular and cellular constituents. […] There is [also] a causal relationship between changes in vascular compliance and the evolution of the collagen/elastin ratio, and the proportion of endothelial and smooth muscle cells. […] During aging, elastin is degraded and the collagen/elastin ratio increases. As a result, the elastic recoil of the vessel wall decreases […] The results from the investigation of aging of mitotic cells suggest that the evolution of several cell compartments through division constitutes a developmental process where cells are modified with […] consequent repercussions on cell function and cell interactions; this remodeling creates a drift that contributes to aging and senescence of the organism.”