Ukrainica Bioorganica Acta 1—2 (2004) 3—12 www.bioorganica.org.ua Do mammals die young!? An agedependent mechanism of mammals selfdestruction O. G. Boyko MultiВranched Centre of Science & Technology «Agrobiotech» 50 Kharkivski highway, Kyiv, 02160, Ukraine Abstract. It is hypothesized the first multicellular organisms arisen on the Earth have inherited neither cell aging nor programmed cell death mechanisms from singlecellular ancestors possessing practically unlimited longevity. Both aging and aginginduced death are later evolutionary acquisitions. They are typical only for some phyla, and the majority of nowadays species of multicellular organisms are potentially immortal. Cell aging mechanisms in multicellular organisms can be somewhat involved in agedependent mechanisms of self destruction, but they cannot determine themselves the organism’s aging and longevity. An agerelated mecha nism of mammal selfdestruction appears in the evolutionary lineage from mammallike reptiles Synapsida to mammals in addition to existing systemic and cellular mechanisms of aging. Such agerelated mechanism direct ing the selfdestruction of mammal’s organism is a result of some evolutionary events leading to the «postmitot ic brain» development in mammals. In this minireview, recent results relevant to this hypothesis are surveyed and some approaches to intervening in the proposed process are discussed. Keywords: aging, hypothesis, mammals, birds, exogenous organospecific RNAs, postmitotic brain. Introduction. The ultimate aim of gerontology lachev’s version, potential immortality has alrea researches is to make human aging optional. dy considered not as a luxury, but as a fatal dan Therefore, the initial purpose of this work was ger for population, contrary to initial Weismann’s to consider the most important facts and ideas and conception. to show a possibility for further development of Skulachev [2] underlines that when Weismann the Dilman’s ontogenetic aging model. However, had formulated his «tough» hypothesis postulat in the process of work there was a need to revise ing that the death of ancestors frees room for bet some dogmas and common notions; as a result, we ter adapted progenitors, he relied especially on propose a hypothesis of the initial immortality of considerations of biological expedience. multicellular organisms and an agedependent Indeed, every new trait appearing in the off mechanism of selfdestruction of mammals spring would be inevitably diluted by the ocean of (AMSM). old traits carried by parents, grandparents, etc., if In our proposed hypothesis some Weismann’s they were immortal. In other words, the immor views on the aging and death as «something sec tality of individuals belonging to any biological ondary that appeared in the process of adapta species would block the progressive development tion» (they have been recently reanimated by of this species. Skulachev) are taken as an axiom [1]. In Sku According to Skulachev, an aging is nothing but the programmed death at the level of the Corresponding author. Email address: whole organism (phenoptosis). [email protected] We are to agree with this maxim. Skulachev asserts that the death caused by aging clears the © O. G. Boyko, 2004 3 O. G. Boyko population of ancestors and frees space for proge Within the framework of the hypothesis of the ny carrying new useful traits. initial immortality of multicellular organisms, I Like any important function, the aging is medi postulate, that: ated by several molecular mechanisms working 1. Phenoptosis function in Prokaryota and sin simultaneously. At least three such mechanisms glecelled Eukaryota is carried out by the mecha have been postulated already: 1) telomere short nism known as programmed cell death. In the ening due to telomerase suppression at early process of evolution the programmed cell death embryogenesis stages; 2) agerelated activation of has arisen in prokaryotes as a mechanism of a mechanism inducing the synthesis of heat shock antiviral protection and has been kept throughout proteins in response to denaturing stimuli; and eukaryote evolution from singlecellular organ 3) incomplete suppression of generation of reac isms to multicellular ones [4—6]. In multicellular tive oxygen species (ROS) with inadequate scav organisms this mechanism has been adapted for enging of already existing ROS. None of these defense, development, homeostasis, and realiza phenomena can kill the organism, but they weak tion of other important vital functions. en it, the changes becoming crucial under certain 2. Following the origination of the first multi extreme conditions [2]. cellular organisms, some of them get rid of the Actually, both Skulachev and a majority of program of selfdestruction and obtain their authors are sure the aging phenomenon is potential immortality. In a primitive multicellu reduced to a small number of single cellular and lar organism the cell transforms into a part of a organism processes defining the aging rate. These complex system. However, this cell may also processes include apoptosis, ageassociated accu inherit their programs of cellular aging and pro mulation of mutated mtDNA molecules, defects in grammed cell death from its singlecellular ances cell cycle control, mitotic dysregulation, genome tor(s). These mechanisms can cause aging and instability, telomere shortening, ageassociated destruction of this cell, but not of the organism as changes in levels of neurohumoral regulation and a whole. Nowadays there are several such immor other cell and organism pathologies [3]. tal relicts. It is a hydra, some species of medusae Moreover, Skulachev proposes that a succes and a number of other organisms. A freshwater sion of events including mitoptosis, apoptosis, hydra is a very good example. In optimal condi and organoptosis to be completed by a stage tions the hydra lives a long time, without varying more — programmed death at the supracellular in any way and without aging. In the top of level (the level of the whole organism), i.e. by hydra’s body there is a zone with many proliferat phenoptosis. ing cells. From here «newborn» cells migrate to In this paper I oppose to these views on aging: the ends of the body where they continue to pro there are a lot of socalled nonageing species liferate forming the ectoderm and endoderm among multicellular organisms which actually (muscles, nervous cells and other ones). However, are not subjected to aging and possess potential they are soon ready to be superseded by new immortality. One may assert the existence of such young cells coming from intensive proliferation immortality in that time continuum to which in a zone. This process goes continuously, and the human brain the concept of boundless longevity is hydra lives a long time without aging symptoms bound. For example, we can mention about the under a single indispensable condition: it needs known longevity of the giant sequoia (Sequoia favourable environment. During some slight nat dendron giganteum) (about 4 thousand years) or ural cataclysm — changes of temperature or longevity of any raspberry or grapes clone. appearance of some water contaminants the cell Potential immortality of these species are not division is retarded, the hydra becomes a target of interfered neither with incomplete suppression of aging and perishes. Therefore, the hydra possess ROS generation, nor with telomere shortening es only potential immortality. due to suppression of telomerase as well as by 3. Taking these data into consideration the other cell and organismrelated processes being author asserts the first multicellular organisms on aging factors according to the Skulachev’s con the Earth have inherited from singlecellular ception. eukaryotes their mechanisms of cellular aging and 4 Ukrainica Bioorganica Acta 1—2 (2004) Do mammals die young!? programmed cell death; these organisms possess among fishes, reptiles (anapsids), and sauromor practically unlimited longevity. Aging and death phic animals (the evolutionary lineage from from aging are more late evolutionary acquisitions. amphibians to dinosaurs and birds). No theri They are typical only in some phyla. Moreover, it is omorphic animal species (in the evolutionary line possible to assert that the majority of nowadays age from amphibians to mammallike reptiles and existing species of multicellular organisms are mammals) are known with negligible senescence, potentially immortal. Finch and Austad proposed both among fossil species and modern mammals. [7] minimal criteria for the lack of senescence: (1) no According to leading modern conceptions, at observable increase in agespecific mortality rate least two or even several evolutionary lineages of or decrease in reproduction rate after sexual matu amphibians have developed sets of reptilian traits. rity and (2) no observable agerelated decline in Almost all researchers are agree upon the exis physiological capacity or disease resistance. There tence of two independent evolutionary branches are many such species of fishes, turtles, birds, and of tetrapods — theriomorphic animals, crowned vascular plants. In these multicellular organisms by mammals, and sauromorphic ones, progenitors the aging is so slow that no agingrelated changes of dinosaurs and birds. are detectable («negligible senescence»). During their evolution theriomorphic animals 4. If the aging and death from aging are typical have developed such phenomenon as the postmi only for some phyla, these phyla might also pos totic brain. Today there is no satisfactory