The programmed aging paradigm: How we get old

Abstract

According to the traditional explanations ("old paradigm"), aging is due to the progressive accumulation of heterogeneous damages that are insufficiently contrasted by natural selection. An opposite interpretation ("new paradigm") sees aging as selectively advantageous in terms of supra-individual natural selection, and this implies the indispensable existence of genetically controlled specific mechanisms that determine it. The aim of this work is to expound synthetically the progressive alterations that mark the aging by showing how these changes are clearly defined and regulated by genes. The possibility of such a description, based on sound evidence, is an essential element for the plausibility of the new paradigm, and a fundamental argument against the tenability of the old paradigm.

Non-programmed Versus Programmed Aging Paradigm

“…Aging may be described as the result of the gradual decline of cell turnover, resulting in a progressive atrophy of all tissues and organs [44,82], associated with the increase of the percentage of cells in cell senescence (on / off and gradual, s. below). In any case, cell turnover and its gradual decline are clearly subjected to a genetic regulation that is certainly very complex and sophisticated.…”

Aging of perennial cells and organ parts according to the programmed aging paradigm

“…The aforementioned mechanisms that determine a progressive age-related fitness impairment have been described in brief in another paper (Libertini 2014), and, here, only a brief mention of them will be given.…”

“…The replication of these cells is subject to genetically determined and regulated limitations, due to telomerase inhibition and therefore to restrictions in telomere length restoration (Libertini 2009a). Telomere shortening leads to an increasing probability of the complete blocking of cell duplication capacity plus a wide impairment of cell functions (Fossel 2004), i.e., cell senescence (Ben-Porath and Weinberg 2005), and also to a progressive impairment of cell functions, i.e., gradual cell senescence (Fossel 2004;Libertini 2014Libertini , 2015b. The progressive limitation for stem cells in replacing cells eliminated by PCD leads to a gradual slowing of cell turnover.…”

“…The progressive limitation for stem cells in replacing cells eliminated by PCD leads to a gradual slowing of cell turnover. This, together with the effects of on/off and gradual senescence, progressively determines an atrophic syndrome for all organs and tissues that is characterized by the following: a) "Reduced mean cell duplication capacity and slackened cell turnover b) Reduced number of cells (atrophy) c) Substitution of missing specific cells with nonspecific cells d) Hypertrophy of the remaining specific cells e) Altered functions of cells with shortened telomeres or definitively in noncycling state f) Alterations of the surrounding milieu and of the cells depending from the functionality of the senescent or missing cells g) Vulnerability to cancer because of dysfunctional telomere-induced instability ..." (Libertini 2014) A fair objection against this mechanism, in particular regarding its ability to explain all aging features, is that this would be contradicted by the existence of cell types and organ parts that are not subject to renewal but show aging alterations as cell types and organs that are subject to cell turnover.…”

“…In this regard, in an aforementioned paper (Libertini 2014), a partial and short answer has already been given, but given the importance of the subject, it is necessary that this answer is deepened and enriched here with further elements.…”