A senescent cell is not simply an aged cell but a cell in a particular and well-defined condition. In fact, cell senescence is a specific program triggered in normal cells by various factors [1], such as telomere shortening [2], other forms of DNA damage without alterations of telomere status, oxidative stress, cellular stress, subopti- mal culture conditions, and activated oncogenes [3, 4]. Cell senescence is characterized by: (i) inhibition of proliferative activity (replicative senescence) [5]; (ii) typ- ical general alteration of cell functions [6-9] (“Senescence-related chromatin remodelling leads to profound transcriptional changes” [10]); (iii) alterations in extracellular secretion (senescence-associated secreto- ry phenotype, SASP) [11, 12]; (iv) resistance to apoptosis [9, 13]. In the past, cell senescence was conceived as a one- step phenomenon. Now, it appears that, at least for cell senescence stimulated by certain types of stress, it first goes through the phase in which it is reversible if the stress factor is reduced or eliminated [10]. After this phase, cell senescence becomes irreversible, although under artificial conditions, for example, upon simultaneous inactivation of p53 and expression of p16 Ink4a , it appears reversible [14]. This confirms that cell senescence is not a result of accumulation of harmful substances or events but a genetically regulated process that has been defined as a cellular program [1]. The number and fraction of senescent cells (identi- fied as cells expressing p16 Ink4a ) increases with age [15- 17]. This increase in the content of senescent cells is clearly related to aging manifestations and age-related diseases [18-20]. Furthermore, elimination of such cells reduces and improves aging manifestations [19-21]. This has generated the motivated firm belief that selective elimination of senescent cells with appropriate (senolytic) drugs is an important and useful therapeutic goal [21-23]. Interesting results have already been obtained using (i) dasatinib + quercetin in mice with idiopathic pul- monary fibrosis [24]; (ii) senolytic compound UBX0101 in transgenic mice with post-traumatic osteoarthritis [25]; (iii) FOXO4 peptide in naturally aged and fast aging XpdTTD/TTD mice and in mice with doxorubicin- induced chemotoxicity to restore fitness, fur density, and renal function or to counteract chemotoxicity, respective- ly [26]; (iv) siRNAs or the small molecule ABT-737 in ISSN 0006-2979, Biochemistry (Moscow), 2018, Vol. 83, Nos. 12-13, pp. 1477-1488. © Pleiades Publishing, Ltd., 2018. Published in Russian in Biokhimiya, 2018, Vol. 83, No. 12, pp. 1812-1826. REVIEW 1477 * To whom correspondence should be addressed. Elimination of Senescent Cells: Prospects According to the Subtelomere-Telomere Theory G. Libertini 1,a *, N. Ferrara 1 , G. Rengo 1 , and G. Corbi 1 1 Federico II University, Department of Translational Medical Sciences, 80138 Naples, Italy a e-mail: giacinto.libertini@yahoo.com Received May 1, 2018 Revision received August 23, 2018 Abstract—Cell senescence is an artificially reversible condition activated by various factors and characterized by replicative senescence and typical general alteration of cell functions, including extra-cellular secretion. The number of senescent cells increases with age and contributes strongly to the manifestations of aging. For these reasons, research is under way to obtain “senolytic” compounds, defined as drugs that eliminate senescent cells and therefore reduce aging-associated decay, as already shown in some experiments on animal models. This objective is analyzed in the context of the programmed aging paradigm, as described by the mechanisms of the subtelomere-telomere theory. In this regard, positive effects of the elimi- nation of senescent cells and limits of this method are discussed. For comparison, positive effects and limits of telomerase activation are also analyzed, as well of the combined action of the two methods and the possible association of opportune gene modifications. Ethical issues associated with the use of these methods are outlined. DOI: 10.1134/S0006297918120064 Keywords: aging, cell senescence, gradual cell senescence, senolytic drugs, telomerase, subtelomere, programmed aging the- ory, phenoptosis