There are two antithetical general explanations for “aging” [1], here precisely defined as “age-related progressive fitness decline (i.e., mortality increase)”.They are totally different, have very important opposed implications and, therefore, deserve to be referred to as “paradigms”. The first (“Old Paradigm”) explains aging as the effect of various factors that are insufficiently opposed by natural selection [2].The second (“New Paradigm”) explains aging as a physiologic phenomenon determined and favored by supra-individual selection in particular conditions [3].The two paradigms, by definition, are incompatible with each other.The New Paradigm predicts and requires the existence of specific mechanisms, genetically determined and regulated, which cause aging [3].Here, I want to expound the evidence about how we age according to the New Paradigm, i.e. a general description of aging process in our species (and in mammals in general) on the basis of mechanisms genetically determined and regulated.

REFERENCES: [1] Goldsmith T. The Evolution of Aging (3rd ed.). Azinet Press, USA 2013; [2] Kirkwood TBL, Austad SN. Why do we age? Nature 2000; 408:233-8; [3] Libertini G. Empirical evidence for various evolutionary hypotheses on species demonstrating increasing mortality with increasing chronological age in the wild. TheScientificWorld Journal 2008; 8:183-93; [4] Kerr JFR et al. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26:239-57; [5] Libertini G. The Role of Telomere-Telomerase System in Age-Related Fitness Decline, a Tameable Process, in Telomeres: Function, Shortening and Lengthening, Nova Sc. Publ., New York 2009; [6] Alberts B. et al. Essential Cell Biology, 4th ed., Garland Science, 2013; [7] Blackburn EH. Telomere states and cell fates. Nature 2000; 408:53-6; [8] Fossel MB. Cells, Aging and Human Disease. Oxford University Press, New York 2004; [9] Robin JD et al. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev 2014; 28:2464-76. [10] DePinho RA. The age of cancer. Nature 2000; 408:248-54; [11] Griffiths CEM. Aging of the Skin. In: Tallis, RC et al. (eds), Brocklehurst’s Textbook of Geriatric Medicine and Gerontology (5th Ed.). Churchill Livingstone, New York 1998; [12] Berger JW et al. Age-related macular degeneration, Mosby (USA) 1999; [13] Libertini G. The programmed aging paradigm: How we get old. Biochem (Mosc) 2014; 79(10):1004-16; [14] Libertini G. Prospects of a Longer Life Span beyond the Beneficial Effects of a Healthy Lifestyle. In Handbook on Longevity: Genetics, Diet & Disease, Nova Science Publishers Inc., New York 2009; [15] Flanary B. Telomeres: Function, Shortening, and Lengthening. In Telomeres: Function, Shortening and Lengthening, Nova Science Publishers Inc., New York 2009.

How we age according to Programmed Aging ParadigmGiacinto Libertini (Independent Researcher, giacinto.libertini @ tin.it, www . r-site.org/ageing)

IAGG-ER 8th Congress – 23-26 April 2015, Dublin, Ireland

Cell deathby PCD

Duplication of stem cells

CELL TURNOVER

VERY QUICKVERYSLOW

SLOWQUICK

1) CELL TURNOVER: A cell may dies by necrosis or by one of various types of Programmed Cell Death (PCD). Apoptosis is a type of PCD for the first time described and clearly differentiated from necrosis in the observation of the hepatocytes in a healthy liver [4]. Other types of PCD are: a) the keratinization of epidermis or hair cells; b) the detachment of cells from the lining of intestines or other body cavities; c) osteocytes phagocytized by osteoclasts; d) the transformation of erythroblasts in erythrocytes and their subsequent removal by macrophages; etc.In vertebrates, a pivotal function of PCD is related to cell turnover in healthy adult organs, as well documented for many tissues and organs [5]. The rhythm of cell turnover varies greatly depending on cell type and organ. In the intestinal epithelium “cells are replaced every three to six days”, while “bone has a turnover time of about ten years in humans” [6]. In cells where telomerase is not active, an infinite number of duplications is impossible for the progressive telomere shortening [5].

With the passage of time (and with very different rhythms, varying for cell types and organs), in a tissue: - the percentage of cells in senescent state increases;- the percentage of cells with functions more or less affected by telomere shortening and the consequent interference in the subtelomeric region increases [5]. Figure 8-2 (partial) from [8]: “a

modicum of cells display varying degrees of senescent change”

This leads, for each tissue and organ, to an “atrophic syndrome”, which is characterized by [5]:a) reduced mean cell duplication capacity and slackened cell turnover;b) reduced number of cells (atrophy);c) substitution of missing specific cells with non-specific cells;d) hypertrophy of the remaining specific cells;e) altered functions of cells with shortened telomeres or definitively in non-cycling 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 [10].

2) “ON/OFF” CELL SENESCENCE: In a cell in “cycling” state, the telomere, whatever its length, oscillates between two phases: “capped” and “uncapped” (by a protein complex).The probability of the uncapped phase is inversely proportional to the relative reduction of telomere length. In the uncapped phase, the cell is vulnerable to the transition to non-cycling state, i.e. to the activation of cell senescence program [7]. Figure 1 from [7]

3) “GRADUAL” CELL SENESCENCE: The progressive shortening of telomeres has another effect. The telomere is covered (capped) by a protein complex that, as the telomere shortens, hides the subtelomeric DNA and causes transcriptional silencing.“As the telomere shortens, the hood slides further down the chromosome … the result is an alteration of transcription from portions of the chromosome immediately adjacent to the telomeric complex, usually causing transcriptional silencing … These silenced genes may in turn modulate other, more distant genes (or sets of genes). There is some direct evidence for such modulation in the subtelomere ...” [8]This is confirmed by a recent study [9].

Figure 7 from [5]

Programmed cell death, “on/off” and “gradual” cell senescence, cell duplication limits (variable according to cell types and influenced by various physiological and pathological events), cell turnover and its limitations (variable depending on the cell types) are all phenomena genetically determined and regulated [13].

EXAMPLE OF CELLS WITH TURNOVER: EPIDERMAL AND DERMAL CELLSHuman epidermis turnover is determined by stem cells located in the dermal-epidermal junction, a corrugated surface. In old subjects, dermal-epidermal junction is flattened, an indirect sign of the reduction of epidermis stem cells, and the rate of epidermal renewal is reduced. In derma, as a likely consequence of the exhaustion of specific stem cells, a general reduction of all its components (melanocytes, Langerhans cells, dermal fibroblasts, capillaries, blood vessels within the reticular dermis, mast cells, eccrine glands, hair. etc.) is reported and nails grow more slowly [11].“The study of aging skin is one that presents a paradigm for aging of other organs.” [11]

D-E junction

EXAMPLE OF CELLS WITHOUT TURNOVER: RETINA PHOTORECEPTORSPhotoreceptor cells (cones and rods) are highly differentiated nervous cells with no turnover, but metabolically depending on other cells with turnover, retina pigmented cells (RPC), which are highly differentiated gliocytes.Without the macrophagic activity of RPC, photoreceptor cells cannot survive [12]. The age-related decline or RPC turnover causes the death of photoreceptor cells, which is more clinically evident in macula function (age-related macular degeneration) [13]. Analogous hypothesis has been proposed for the neurons of central nervous system, microglia cells, and the genesis of Alzheimer’s disease [8, 14, 15].

The mechanisms, genetically determined and regulated, here summarized and better expounded elsewhere [13], clearly cause an age-related progressive deterioration of all functions, namely aging. They are predicted by the New Paradigm and indeed are essential for its validity.On the contrary, they are not expected by the Old Paradigm and are in complete contrast with it.

Differences in cell turnover speed

The explanation of aging through the New Paradigm allows: - A rational and consistent interpretation of all aging manifestations;

- The prospect of being able to change and obtain a full control of aging through scientific procedures which are technically feasible [5, 14].