The Role of Telomere-Telomerase System in Age-Related Fitness Decline , a Tameable Process

In our body there is a continuous cell turnover. Every day innumerable cells die by programmed cell death, in particular apoptosis, and are replaced by others deriving from stem cells. With the passing of time, this turnover is limited by sophisticated mechanisms, genetically determined and regulated, which control the telomere-telomerase system and therefore cell duplication capacity (replicative senescence) and overall functionality (cell senescence). Alterations of cell turnover mechanisms cause dramatic syndromes, such as dyskeratosis congenita and Werner syndrome, while the normal age-related slowdown and stopping of this turnover causes a fitness decline that is defined senescence in its more advanced expressions. The fitness decline documented in the wild for many species should not be confused with the mortality increment observed for animals, as Caenorhabditis elegans and Drosophila melanogaster, in artificial conditions at ages non-existent in the wild. Many species are not subject to this fitness decline and, in the case their individuals reach very old ages in the wild, are defined as ageless animals or species with ‘negligible senescence’. For some of them, the functionality of the telomere-telomerase system has been documented as unvaried at older ages. Indeed, the fitness decline appears not an inevitable decay but a very sophisticated function, favoured for its greater inclusive fitness in particular selective conditions, and, being a function, in principle modifiable and governable. This leads to the prospect that senescence will be tamed in the not too distant future, in particular by control of, or more audaciously, by a modification of, the genetic determinants of the telomere-telomerase system. Such a prospect is radically different from the present advances in medical cures that are only increasing the proportion of disabled ultra-octogenarians. Giacinto Libertini 2 Behind the Scenes: Introduction When Darwin proposed the hypothesis of evolution by natural selection, two big problems undermined the reliability of the great theory. The first was the existence of insect species with social organisation (bees, ants, etc.). If natural selection favours individuals with greater fitness and reproductive success, how can one explain the fact that worker individuals of these species nurse the progeny of queens and do not procreate themselves? What possible selective mechanisms can favour the genes determining such odd behaviour? Darwin, the father of modern biology, did not know how to answer: as an improvised patch for a wonderful new dress with a bad tear, he justified all this by maintaining that such behaviour was favoured because it was advantageous for the species [1]. He was wrong, and the correct answer was discovered nearly a century later, as will soon be discussed. The second problem was even more serious. For many species, Homo sapiens included, an increase in chronological age is accompanied by a fitness decline in the wild. That is to say, mortality rates increase with age in the wild [2,3,4,5,6,7,8,9]. Regarding this fitness decline, referred to as “aging” in its more advanced expression (a popular and terrible name), if natural selection favoured the fittest, how was this explicable? Darwin had two alternatives, both difficult and fraught with implications. The first (nonadaptive hypothesis) demanded the admission that natural selection was not able to favour genes suited to keeping fitness stable at increasing ages. However, was it possible that natural selection, which is thought to have moulded the eye, brain, hand and numberless marvels in numberless animal, plant and microbe species, failed in the task of keeping fitness stable at greater ages? Moreover, if this is the case, then why has this hypothetical incapacity of selection been greater for some species that age quickly and lesser for other species which age slowly or even not at all? The other possibility (adaptive hypothesis) was that this fitness decline had some unknown evolutionary advantage. This hypothesis seemed even more arduous: how could an anticipated death be evolutionarily advantageous? Who could maintain such a thing without being considered a little muddled, or worse? Darwin could not give an answer to the second problem, thus it was aptly named Darwin’s dilemma [10]. Some years later, August Weissmann, using extraordinary intuition, tried to give an answer. Unfortunately, he did not formulate a clear exposition or give solid scientific proofs, although he did hint that the anticipated death of old individuals was beneficial because this gave more space to new generations which was useful for the evolution of species [11,12]. In short, Weissmann was a supporter of the adaptive hypothesis of fitness decline, although he later disavowed it [12,13]. Furthermore, about the mechanism underlying this decline, he observed that the cells of the various organs and tissues were renewed continuously and that when this turnover slackened or stopped, the organs or tissues reduced or lost their functionality with negative effects on fitness [12]. His adaptive hypothesis was original but not well inferred from a theoretical viewpoint. Moreover, as common experience testifies, all inanimate things deteriorate with the passing of time, so why not assume that living beings, too, are subject to the same inexorable law? In fact, “common sense” seems to strongly suggest that the nonadaptive hypothesis of fitness The Role of Telomere-Telomerase System in Age-Related Fitness Decline. 3 decline is correct, even if this requires the admission that natural selection is incapable of solving this specific problem. On the contrary, the cell turnover mechanism hypothesised by Weissmann for the aging was easier to understand and accept but it had an unhappy fortune, too, at least for the next 70 years. Indeed, an illustrious Nobel prize winner, Alexis Carrel, demonstrated that cells explanted and cultivated in vitro multiplied an unlimited number of times [14], meaning that Weissmann’s hypothesis was groundless and unacceptable. Poor Weissmann with his intuitions seemed to miss every time! In 1961 an obscure researcher, Leonard Hayflick, cultivated fibroblasts in vitro and discovered that they multiplied a limited number of times, a finding in clear contrast with Carrel’s results. After having excluded any factor as a possible cause of such stoppage in cell duplication, he decided to publish his findings. However, the authoritative journal to which the paper was submitted rejected it, with the statement that it was a priori unacceptable since the results were in plain contrast with what had been definitively demonstrated and what was accepted as scientifically sound. Fortunately, Hayflick was stubborn and succeeded to publish his paper in a less authoritative journal which was more open to new ideas [15]. Carrel’s observations (likely due to errors in cell culture methodology) were overthrown and Weissmann’s hypothesis recovered its value! Hayflick stated in 1977 that the limits in cell duplication (Hayflick limit) were the likely cause of the aging: “. if normal animal cells do indeed have only a limited capacity for division in cell culture, the manifestations of aging might very well have an intracellular basis. ” [16]. However, this statement was in contrast with other ideas that by this time were imposing themselves about the aging [17], i.e.: “mutation accumulation” theory — “Aging” is due to the effects of harmful mutations, accumulated over evolutionary time, manifesting themselves at older ages when, in the wild, survivors are few or absent and, consequently, selective forces are too weak to eliminate them [18,19,20,21,22]. “antagonistic pleiotropy” theory — “Senescence” is caused by pleiotropic genes with beneficial effects at early ages and deleterious effects at later ages [23,24]. “disposable soma” theory — “Aging” has environmental or somatic and not genetic causes, and evolutionary responses to them are increasingly limited at older ages by physiological, biochemical or environmental constraints. Therefore, in the evolutionary search of an optimal allocation of metabolic resources between somatic maintenance and reproduction, the second is preferred [25,26]. In a relatively recent paper, Hayflick, as a prophet repudiating himself, did not mention the pivotal importance of cell duplication limits for the mechanisms of aging and instead proclaimed: “Ageing is a stochastic process that . results from the diminishing energy available to maintain molecular fidelity. This disorder has multiple aetiologies including damage by reactive oxygen species. ” [27] In the years 1970-76, I was a simple student of medicine, rich in a wide ignorance and in the foolhardiness of which the ignorant persons enjoy, but —merit among the faults— was strongly struck by Hayflick’s results that I considered of extreme importance for aging studies. I became an enthusiast of Hayflick’s discovery and of its implications and remained Giacinto Libertini 4 firm in this belief even when Hayflick diminished or denied the importance and the implications of his results. Stimulated by them, I tried to explain, in precise terms of natural selection, the advantage of a quicker turnover of generations that seemed to me the automatic consequence of the Hayflick limit or, in the case that this limit was unimportant, the advantage of the evident restraints in the individual duration of life for many species, man included, whichever the mechanism causing those restraints was. Knowing what Weissmann had hinted at, and stimulated by the suggestions of two botanists [28,29], I formulated a mathematical model demonstrating with precision how a quicker generation turnover allowed a quicker diffusion of a favourable gene within a species. In numerical terms, this study modelled the spreading velocity of a gene within a species, the increment by x% of gene advantage o