The Necessity of a Revolution in Gerontology and Geriatrics Giacinto Libertini, Graziamaria Corbi, Nicola Ferrara Federico II Univ., Dept. of Translational Medical Sciences, Naples, Italy International Association of Gerontology and Geriatrics European Region (IAGG-ER) Congress – 23-25 May 2019, Gothenburg, Sweden

The subject of this presentation is normal aging, that is, only persons with healthy lifestyles who nevertheless are always affected by age-related progressive alterations of their functions that eventually lead them to death. If we consider only normal aging, disregarding palliative or symptomatic care, medicine is virtually impotent and geriatrics appears a disastrous branch of medicine, indeed a medical activity that is always ineffective. [1] Fillit HM, et al (eds) (2016) Brocklehurst’s Textbook of Geriatric Medicine and Gerontology, 8th edition, Saunders – Elsevier 2/20

Insufficient physical activity Statins, ACEi, sartans, etc. Prevention Alcohol abuse Dyslipidemia Insufficient physical activity Smoke Statins, ACEi, sartans, etc. Diabetes + Hypertension + + + + + - - Etc. + Accelerated aging It is known that: - various factors (“risk factors”: smoke, diabetes, dyslipidemia, insufficient physical activity, etc.) speed up the rhythm of aging; - it is possible to limit or cancel this aging acceleration by avoiding these factors (prevention) or also by appropriate drugs (“protective factors”) [1]. This means avoiding pathological aging and not opposing normal aging [2]. [1] Fillit HM, et al (eds) (2016) Brocklehurst’s Textbook of Geriatric Medicine and Gerontology, 8th edition, Saunders – Elsevier [2] Libertini G, Ferrara N (2016) Possible Interventions to Modify Aging. Biochem (Mosc) 81:1413-28 3/20

In modern medicine, geriatrics treats by ineffective methods and with discouraging results the many disorders afflicting the physiological senile decay. Moreover, aging is not considered a distinct trouble: in the International Classification of Diseases [1, 2] there is no distinct code for aging. So, in the world statistics of death causes, no one of these men can die officially by “aging” [3]. [1] WHO, ICD-10 (2016), http://www.who.int/classifications/apps/icd/icd10online/ [2] WHO, ICD-11 (2018), https://icd.who.int/browse11/l-m/en [3] Wikipedia, World Life Expectancy, www.worldlifeexpectancy.com/sitemap, and World Ranking Total Deaths (2017), www.worldlifeexpectancy.com/world-rankings-total-deaths 4/20

Fourth: Aging does not have specific biochemical mechanisms [4]. This conception is based on some firm beliefs, widely shared and considered as true and indisputable [1-5]: First: Aging is a maladaptive phenomenon because it fatally damages the individual and therefore cannot be favoured by natural selection [1]. Second: Aging is an inevitable and universal phenomenon in the living world [2]. Third: Aging is the cumulative effect of many stochastic distinct degenerative processes [3]. Fourth: Aging does not have specific biochemical mechanisms [4]. Fifth: Aging is not “curable” although it is possible to propose the slowing down of the degenerative processes that constitute it [5]. [1] Kirkwood TB, Austad SN (2000) Why do we age? Nature 408:233-8 [2] Biliski T, et al (2014) The rules of aging: are they universal? Is the yeast model relevant for gerontology? Acta Biochim Pol 61:663-9 [3] Hayflick L (2016) Unlike the Stochastic Events That Determine Ageing, Sex Determines Longevity. In: Rattan S., Hayflick L. (eds) Cellular Ageing and Replicative Senescence. Healthy Ageing and Longevity. Springer, Cham [4] Olshansky SJ, Hayyflick L, Carnes BA (2002) Position Statement on Human Aging. J Gerontol A Biol Sci Med Sci. 57:B292-7 [5] Hayflick L (2004) “Anti-aging” is an oxymoron. J Gerontol A Biol Sci Med Sci 59(6):B573-8 5/20

A “Copernican” revolution in gerontology and geriatrics is necessary. As we will see, these firm beliefs are erroneous because contradicted by fundamental concepts of natural selection and by a huge mass of data. A strong attachment to inveterate ideas and a lack of knowledge of known data and ideas can explain the wide diffusion and the persistence of firm beliefs. A “Copernican” revolution in gerontology and geriatrics is necessary. It must start from the overcoming of these convictions and will transform geriatrics from a failure into the most successful branch of medicine. 6/20

Why are these beliefs wrong? First firm belief: Aging is a maladaptive phenomenon because it fatally damages the individual and therefore cannot be favoured by natural selection. Supra-individual selective mechanisms can favor genes whose action kills the individual where they are or his / its kin. There is a large category of such phenomena, defined as “phenoptosis” [1, 2]. Phenoptotic phenomena are numberless, determined by various causes and mechanisms, and widespread in nature [3]. They affect practically all species, including ours. So, there is no theoretical veto for the idea that aging is an adaptive phenomenon [1, 2]. [1] Skulachev VP (1997) Aging is a specific biological function ... Biochem (Mosc) 62:1191-5 [2] Libertini G (2012) Classification of Phenoptotic Phenomena. Biochem (Mosc) 77:707-15 [3] Finch CE (1990) Longevity, Senescence, and the Genome. University of Chicago Press, Chicago 7/20

only a small minority of species ages. Second firm belief: Aging is an inevitable and universal phenomenon in the living world. The types of life tables in the living world are extremely varied [1] and, as a rule, are examples of phenoptosis [2] or, in some cases, of its absence (negligible senescence) Death after spawning [2] Etc. Aphagy in adult insects [2] Autogeny [2] Death of the male associated with mating / reproduction [2] Aging (“slow phenoptosis” [3]) Endotokic matricide [2] Hormonally triggered senescence in plants [2] Negligible senescence [2] If we define aging as age-related increasing mortality (or decreasing fitness) only a small minority of species ages. [1] Jones OR, et al (2014) Diversity of ageing across the tree of life. Nature 505:169-73 [2] Finch CE (1990) Longevity, Senescence and the Genome, University of Chicago Press, London [3] Skulachev VP (2002) Programmed Death Phenomena: From Organelle to Organism. Ann NY Acad Sci 959:214-37 8/20

This suggests that there are common mechanisms that determine aging. Third firm belief: Aging is the cumulative effect of many stochastic distinct degenerative processes In the human species, and not only in it, the patterns by which aging manifests itself are quite constant and well describable [1, 2]. This suggests that there are common mechanisms that determine aging. This does not exclude that, as for every biological mechanism, random phenomena influence it. [1] Fossel MB (2004) Cells, Aging and Human Disease. Oxford University Press, New York, p. 53 [2] Libertini G (2014) Programmed aging paradigm: how we get old. Biochem (Mosc) 79:1004-16 9/20

The telomere-subtelomere-telomerase system [1, 2] Fourth firm belief: Aging does not have specific biochemical mechanisms The rejection of this idea is based on a large amount of studies. Here only a brief summary will be mentioned. The telomere-subtelomere-telomerase system [1, 2] At each cell duplication if the telomerase enzyme is inhibited, in proportion to the degree of inhibition the telomere shortens and the subtelomere is repressed. If telomerase is not inhibited, as in germ line cells, the telomere will not shorten. [1] Fossel MB (2004) Cells, Aging and Human Disease. Oxford University Press, New York [2] Libertini G (2009) 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 10/20

Oxidation of cell components Oxidation of cell components As telomere shortens, the nucleoprotein cap covering it slides over the subtelomere and represses it. This determines two effects: First effect: Gradual repression of the functions regulated by the subtelomere with progressive impairment of cell functions (gradual cell senescence) [1, 2] The gradual cell senescence also manifests itself with the increase of oxidized substances. This leads to the widespread belief that oxidized substances cause aging [1]. As gradual cell senescence is completely reversible, the opposite is true: “Cells do not senesce because of wear and tear, but because they permit wear and tear to occur because of an altered pattern of gene expression” [1] Oxidation of cell components Cell aging YES! NO! Cell aging Oxidation of cell components [1] Fossel MB (2004) Cells, Aging and Human Disease. Oxford University Press, New York, p. 53 [2] Libertini G (2014) Programmed aging paradigm: how we get old. Biochem (Mosc) 79:1004-16 11/20

Duplication of stem cells Second effect: Increasing probability of activating the cell senescence program [1] which determines: (A) block of replicative capabilities; (B) gradual cell senescence at the highest level [2]. Duplication of stem cells CELL TURNOVER Cell death by PCD Cell replication is essential to maintain the normal balance between cells that die by programmed cell death (PCD) and their replacement. Every second, about 600,000 cells are killed by PCD and replaced [3]. [1] Ben-Porath I, Weinberg R (2005) The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37:961-76 [2] Fossel MB (2004) Cells, Aging and Human Disease. Oxford University Press, New York, p. 53 [3] Reed JC (1999) Dysregulation of Apoptosis in Cancer. J Clin Oncol 17:2941-53 12/20

senile enphysema in an old lung The increase in the number of cells with impaired cell functions, and the reduction of the rhythms of cell turnover causes progressively a general atrophic syndrome of all tissues and organs [1]: “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; … young lung senile enphysema in an old lung [1] Libertini G (2014) Programmed aging paradigm: how we get old. Biochem (Mosc) 79:1004-16 13/20

… 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 [1] ...” [1] DePinho RA (2000) The age of cancer. Nature 408:248-54 14/20

endothelial cells osteoblasts other sensory neuronal cells with turnover spermatogonia olfactory receptor cells bone marrow hair follicle cells intestinal cells alveolar type II cells cardiac myocytes hepatocytes glomerular cells dermis and epidermis cells myocytes pancreatic -cells oral cavity cells atherosclerosis and vascular diseases osteoporosis decline of peripheral sensitive functions diminished fertility, testicular atrophy age-related olfactory dysfunction reduction of various hematic cell types baldness intestinal and gastric atrophy emphysema cardiac insufficiency hepatic atrophy renal insufficiency skin atrophy muscle atrophy latent or mild diabetes atrophy of oral mucosa The decline of cells with turnover means “direct” aging of them [1] Telomere – Subtelomere – Telomerase System The decline of cells with turnover that serve perennial cells causes “indirect” aging of the served cells [1] retina pigmented cells that serve retina photoreceptors lens epithelial cells astrocytes that serve neurons microglia cells that serve neurons Deiter's cells that serve hair cells of cochlea photoreceptor impairment and death eye crystalline lens impairment neuronal impairment and death hair cell impairment and death age-related macular degeneration cataract Parkinson's disease Alzheimer’s disease presbycusis [1] Libertini G (2017) The Feasibility and Necessity of a Revolution in Geriatric Medicine. OBM Geriatrics 1(2). doi:10.21926/obm.geriat.1702002 15/20

There are three methods that appear more promising [1]: Fifth firm belief: Aging is not “curable” although it is possible to propose the slowing down of the degenerative processes that constitute it. If aging is a physiological phenomenon, it is not correct to say “cure” of aging. Aging phenomenon may be modified, not “cured”, with the aim of delaying or even cancelling this process. There are three methods that appear more promising [1]: (1 ) Telomerase activation (2) Elimination of senescent cells (3) Genetic modifications of telomere / subtelomere [1] Libertini G, Ferrara N (2016) Possible Interventions to Modify Aging. Biochem (Mosc) 81:1413-28 16/20

(1) Telomerase activation Telomerase stimulation reverts the effects of gradual cell senescence and counters the decline of cell turnover. In mice, telomerase has been reactivated [1] or activated by opportune drugs [2] or by a reverse transcriptase introduced with an adeno-associated virus [3]. The main obstacle for such research is the worry that the telomerase stimulation may be carcinogenic because the limits in cell duplication are explained as a defense against cancer [4, 5]. However, this explanation is untenable and this fear is wrong [6, 7] [1] Jaskelioff M, et al (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469:102-6 [2] Harley CB, et al (2013) A natural product telomerase activator as part of a health maintenance program: metabolic and cardiovascular response. Rejuvenation Res 16:386-95 [3] Bernardes de Jesus B, et al (2012) Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 4:691-704 [4] Campisi J (2000) Cancer, aging and cellular senescence. In Vivo 14:183-8 [5] Wright WE, Shay JW (2005) Telomere biology in aging and cancer. J Am Geriatr Soc 53:S292-4 [6] Mitteldorf JJ (2013) Telomere Biology: Cancer Firewall or Aging Clock? Biochem (Mosc) 78:1054-60 [7] Libertini G, Ferrara N (2016) Possible Interventions to Modify Aging. Biochem (Mosc) 81:1413-28 17/20

(2) Elimination of senescent cells Telomerase activation does not eliminate senescent cells and these contribute strongly to the manifestations of aging. Many researches are underway for the development of senolytic drugs, that is, capable of eliminating senescent cells, with promising results for various typical aging disorders [1-3]. [1] Yosef R, et al (2016) Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun 7:11190. doi: 10.1038/ncomms11190 [2] Baar MP, et al (2017) Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 169:132-47 [3] Jeon OH, et al (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775-81 18/20

(3) Genetic modifications and their ethical problems With the aim of a radical modification of aging, the elongation of telomeric and subtelomeric sequence near the subtelomere-telomere junction has been proposed as theoretical possibility [1]. This type of intervention, even more than the previous ones, modifies the biological nature of man and is a plausible theme of strong objections that can be ethical / religious / philosophical, but in any case outside the scientific field [1]. [1] Libertini G, Ferrara N (2016) Possible Interventions to Modify Aging. Biochem (Mosc) 81:1413-28 19/20

Thanks for your attention Conclusion The transition from a palliative and ineffective geriatrics to a geriatrics that can radically change or even cancel the aging process is proposable. With the ethical reserves of the case, a revolution in gerontology and geriatrics is therefore possible, and geriatrics can be transformed from the greatest failure to the greatest success of medicine. Thanks for your attention