Allergic and Autoimmune Diseases in the Interpretation of Evolutionary Medicine Giacinto Libertini

1. Allergic and Autoimmune Diseases in the Interpretation of Evolutionary Medicine Giacinto Libertini (M.D., Independent Researcher) www.r-site.org/ageing, www.programmed-aging.org e-mail: giacinto.libertini@tin.it 7th Congress ISEB/SIBE – Rome 2017, August 28-31

2. Epidemiology of the allergic diseases Allergic diseases encompass a group of common chronic, immunomediated diseases: - Persistent allergic asthma is found in roughly 10% of all children and 5% of adults, with great variations across geographic regions[1]. - Hay fever (allergic rhinoconjunctivitis) occurs in roughly 20% of individuals from Western populations [2]. - “Worldwide, respiratory allergic diseases alone, namely asthma and allergic rhinitis, affect nearly 700 million subjects.” [3] - “About 20% of all children develop symptoms of atopic dermatitis at some point in their lives.” [4] - “IgE-associated food allergy affects approximately 3% of the population.” [5] “The impact of allergic diseases is tremendous on affected individuals, their families, and societies. They adversely affect quality of life and increase the rate of comorbid conditions and risk of death, as noticed in asthma. In addition, the economic burden of these diseases is considerable.” [3] [1] Asher MI et al (2006) Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368:733-43. [2] Eriksson J et al (2012) Update of prevalence of self-reported allergic rhinitis and chronic nasal symptoms among adults in Sweden. Clin Respir J 6:159-68. [3] Hendaus MA et al (2016) Allergic diseases among children: nutritional prevention and intervention. Therap Clin Risk Manag 12:361-72. [4] Thomsen SF (2015) Epidemiology and natural history of atopic diseases. Eu Clin Respir J 2:10.3402/ecrj.v2.24642. [5] Valenta R et al (2015) Food allergies: the basics. Gastroenterology 148:1120-31.e4.

3. The current “epidemic” of allergic diseases “Prior to the first description of hay fever in 1870 there was very little awareness of allergic disease, which is actually similar to the situation in pre-hygiene villages in Africa today. … there were no clear reports of an increase in pediatric asthma until 1970. Further the current “epidemic” of food allergy does not appear to have started until after 1990.” [1] Sequential rises in some allergic diseases (from [1], modified). [1] Platts-Mills TAE (2015) The Allergy Epidemics: 1870–2010. J Allergy Clin Immunol 136:3-13.

4. The current “epidemic” of autoimmune diseases There are many autoimmune diseases, defined as an abnormal immune response to a normal body part: Addison’s disease – Agammaglobulinemia - Alopecia areata - Amyloidosis - Ankylosing spondylitis - Anti-GBM/Anti-TBM nephritis - Antiphospholipid syndrome (APS) - Autoimmune hepatitis - Autoimmune inner ear disease (AIED) - Axonal & neuronal neuropathy (AMAN) - Behcet’s disease - Bullous pemphigoid - Castleman disease - Celiac disease - Chagas disease - Chronic inflammatory demyelinating polyneuropathy (CIDP) - Chronic recurrent multifocal osteomyelitis (CRMO) - Churg-Strauss’ disease - Cicatricial pemphigoid/benign mucosal pemphigoid - Cogan’s syndrome - Cold agglutinin disease - Congenital heart block - Coxsackie myocarditis - CREST syndrome - Crohn’s disease - Dermatitis herpetiformis – Dermatomyositis - Devic’s disease (neuromyelitis optica) - Discoid lupus - Dressler’s syndrome – Endometriosis - Eosinophilic esophagitis - Eosinophilic fasciitis - Erythema nodosum - Essential mixed cryoglobulinemia - Evans syndrome – Fibromyalgia - Fibrosing alveolitis - Giant cell myocarditis – Glomerulonephritis - Goodpasture’s syndrome - Granulomatosis with Polyangiitis - Graves’ disease - Guillain-Barrè’s syndrome - Hashimoto’s thyroiditis - Hemolytic anemia - Henoch-Schonlein purpura - Herpes gestationis or pemphigoid gestationis - Hypogammalglobulinemia - IgA Nephropathy - IgG4-related sclerosing disease - Inclusion body myositis (IBM) - Interstitial cystitis - Juvenile arthritis - Juvenile diabetes (Type 1 diabetes) - Juvenile myositis - Kawasaki disease - Lambert-Eaton syndrome - Leukocytoclastic vasculitis - Lichen planus - Lichen sclerosus - Ligneous conjunctivitis - Linear IgA disease (LAD) – Systemic Lupus erythematosus - Lyme disease chronic - Meniere’s disease - Microscopic polyangiitis - Mixed connective tissue disease (MCTD) - Mooren’s ulcer - Mucha-Habermann disease - Multiple sclerosis - Myasthenia gravis - Myositis – Narcolepsy - Neuromyelitis optica - Neutropenia - Ocular cicatricial pemphigoid - Optic neuritis - Palindromic rheumatism - PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus) - Paraneoplastic cerebellar degeneration (PCD) - Paroxysmal nocturnal hemoglobinuria (PNH) - Parry Romberg syndrome - Pars planitis (peripheral uveitis) - Parsonnage-Turner syndrome - Pemphigus - Peripheral neuropathy - Perivenous encephalomyelitis - Pernicious anemia - POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) - Polyarteritis nodosa - Polymyalgia rheumatica - Polymyositis - Postmyocardial infarction syndrome - Postpericardiotomy syndrome - Primary biliary cirrhosis - Primary sclerosing cholangitis - Progesterone dermatitis - Psoriasis - Psoriatic arthritis - Pure red cell aplasia (PRCA) - Pyoderma gangrenosum - Raynaud’s phenomenon- Reactive Arthritis - Reflex sympathetic dystrophy - Reiter’s syndrome - Relapsing polychondritis - Restless legs syndrome (RLS) - Retroperitoneal fibrosis - Rheumatic fever - Rheumatoid arthritis - Sarcoidosis - Schmidt syndrome - Scleritis – Scleroderma - Sjogren’s syndrome - Sperm & testicular autoimmunity - Stiff person syndrome (SPS) - Subacute bacterial endocarditis (SBE) - Susac’s syndrome - Sympathetic ophthalmia - Takayasu’s arteritis - Temporal arteritis/Giant cell arteritis - Thrombocytopenic purpura - Tolosa-Hunt syndrome (THS) - Transverse myelitis - Ulcerative colitis - Undifferentiated connective tissue disease (UCTD) - Uveitis – Vasculitis - Vitiligo - Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis) [1], autism, schizophrenia [2]. [1]en.wikipedia.org/wiki/List_of_autoimmune_diseases; [2] Velasquez-Manoff M (2012) An epidemic of absence. Scribner, New York.

5. Researchers have identified 80-100 different autoimmune diseases and suspect at least 40 additional diseases of having an autoimmune basis. These diseases are chronic and can be life-threatening [1]. In the USA, the National Institutes of Health, including only 24 diseases for which good epidemiologic studies were available, estimates that up to 23.5 million Americans suffer from autoimmune diseases and that the prevalence is rising [2]. The American Autoimmune Related Diseases Association says that 50 million Americans suffer from autoimmune diseases, while cancer affects up to 9 million and heart disease up to 22 million [2]. “NIH estimates annual direct health care costs for autoimmune diseases [autism excluded] to be in the range of $100 billion (source: NIH presentation by Dr. Fauci, NIAID). In comparison, cancer costs are $57 billion (source: NIH, ACS), and heart and stroke costs are $200 billion (source: NIH, AHA).” [2] [1] www.womenshealth.gov/publications/our-publications/fact-sheet/autoimmune-diseases.html [2] www.aarda.org/autoimmune-information/autoimmune-statistics/

6. The incidence of autoimmune diseases has been rising sharply over the past several decades in the Western industrialized countries, particularly in the USA [1]. “Prior to the 1950s, there were a grand total of four cases [of transverse myelitis] reported in the medical literature. Currently, my colleagues at the Johns Hopkins Hospital and I hear about or treat hundreds of new cases every year. In the multiple sclerosis clinic, where I also see patients, the number of cases likewise continues to climb.” [2] In Finland, there are 62.3 new cases of type 1 diabetes per year per every 100,000 children, compared with just 6.2 in Mexico and 0.5 in Pakistan [3]. Figure from [4], modified. [1] Nakazawa DJ (2009) The autoimmune epidemic. Touchstone books, New York. [2] Kerr D. Foreword to [1]. [3] Platts-Mills TA (2015) The allergy epidemics: 1870-2010. J Allergy Clin Immunol 136:3–13. [4] Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911-20.

7. An important particular case: Autism Spectrum Disorders In the USA, in children aged 8 years, the frequency of autism for 2010 was 1:68 and the frequency increased by 78% from 2002 to 2008 [1]. “The Autism Speaks organization estimates in the USA that the current costs of autism reach $137 billion per year, a number that has increased more than threefold since 2006.” [2] There is growing evidence that autism should be classified among the autoimmune diseases [3-5]. [1] Forrester JV et al (2008) Immune privilege or privileged immunity? Mucosal Immunol 1:372-81. [2] Gottfried C et al (2015) The Impact of Neuroimmune Alterations in Autism Spectrum Disorder. Front Psychiatry 6:121. [3] Careaga M, Ashwood P (2012) Autism spectrum disorders: from immunity to behavior. Methods Mol Biol 934:219-40. [4] Gesundheit B, et al (2013) Immunological and autoimmune considerations of Autism Spectrum Disorders. J Autoimmun 44:1-7. [5] Mead J, Ashwood P (2015) Evidence supporting an altered immune response in ASD. Immunol Lett 163:49-55.

8. A necessary question: This a congress of Evolutionary Biology not of Medicine! Why are we speaking of medical problems in a congress of Evolutionary Biology? Well, we cannot understand allergic and autoimmune diseases without taking into account the concepts of Evolutionary Medicine [1-10], which is part of Evolutionary Biology! [1] Williams GC, Nesse RM (1991) The dawn of Darwinian medicine. Quart Rev Biol 66:1-22. [2] Nesse RM, Williams GC (1994) Why we get sick. Times Books, New York. [3] Stearns SC (ed) (1999) Evolution in health and disease, 1st ed. Oxford University Press, Oxford (UK). [4] Trevathan WR et al (eds) (1999) Evolutionary Medicine. Oxford University Press, New York. [5] Trevathan WR et al (eds) (2008) Evolutionary Medicine: new perspectives. Oxford University Press, New York. [6] Stearns SC, Koella JC (eds) (2008) Evolution in health and disease, 2nd ed. Oxford University Press, Oxford (UK). [7] Trevathan WR et al (2008) Introduction and overview of Evolutionary Medicine. In: Trevathan WR, Smith EO, McKenna JJ (eds) Evolutionary Medicine: new perspectives. Oxford University Press, New York. [8] Eaton SB et al (1988) The paleolithic prescription: a program of diet & exercise and a design for living. Harper & Row, New York. [9] Price WA (1939) Nutrition and Physical Degeneration. Paul B. Hoeber, New York and London. [10] Libertini G (1983) Ragionamenti Evoluzionistici. Società Editrice Napoletana, Naples (Italy). English Edition (2011): Evolutionary Arguments. Azinet Press, Crownsville (USA).

9. If "Nothing in biology makes sense, except in the light of evolution"[1] is true, why "Nothing in medicine makes sense, except in the light of evolution”[2] should not be true? “Evolutionary Medicine is the enterprise of using evolutionary biology to address the problems of medicine”[3]. Evolutionary Medicine is not an alternative medicine (like homeopathy, iridology, etc.), but a Medicine that is more thoroughly scientific in that it involves the concepts of Evolutionism. If Medicine ignores the principles of evolution, it is only partially scientific! [1]Dobzhansky T (1973) Nothing in biology makes sense except in the light of evolution. Am Biol Teach 35:125–9. [2] Varki A (2012) Nothing in medicine makes sense, except in the light of evolution. J Mol Med (Berl) 90:481-94. [3] Nesse RM, in: Trevathan et al. eds (2008)Evolutionary Medicine: new perspectives. Oxford Univ. Press, New York, Ch. 23.

10. In Evolutionary Medicine, the concept of “mismatch” is fundamental: If a species is adapted to a certain range of conditions (including diet, environmental conditions, interrelationships with other living beings, etc.), defined, for the sake of brevity, as “ecological niche”, any rapid (in evolutionary terms!) change in the ecological niche is a potential source of dysfunctions, i.e., diseases, because there is no adaptation to the new conditions [1, 2]. This is defined as “mismatch” [3]. [1] Libertini G (1983) Ragionamenti Evoluzionistici. Società Editrice Napoletana, Naples (Italy). English Edition (2011): Evolutionary Arguments. Azinet Press, Crownsville (USA). [2] Libertini G (2009) Prospects of a Longer Life Span beyond the Beneficial Effects of a Healthy Lifestyle, in: Handbook on Longevity: Genetics, Diet & Disease. Nova Science Publ. Inc., New York. [3] Eaton SB et al(1988) The paleolithic prescription: a program of diet & exercise and a design for living. Harper & Row, New York.

11. Let us now examine the case of allergic and autoimmune diseases within the framework of Evolutionary Medicine. These disorders are unknown or very rare diseases under natural conditions or before the XIX century in western societies. Therefore, in general, genetic defects cannot be their primary causes: only changes in the ecological niche to which our species is adapted can be their primary causes. There are many mismatches between our adaptation and the modern conditions of life.

12. In order to understand what kind of changes cause immune system disorders, it is important to state first a foremost evolutionary concept. The common belief is to think of natural selection only in terms of individual selection. However, every single individual hosts, either inside or on the body, or otherwise has close interactions with, countless bacteria, viruses, fungi, intestinal parasites, etc. Taking into account the bacteria alone, their number has been estimated to be 3.8*1013, in our species, a little greater than the number of our body cells, which is roughly 3*1013[1] (though an old estimate proposed a 10:1 ratio) [2]. “There are at least as many microbial as there are human cells in our bodies, and the vast majority of unique genes are microbial. As such, we can view ourselves as holobionts.” [3] HUMAN HOLOBIONT = . . . [1] Sender R et al (2016) Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell 164:337-40. [2] Savage DC (1977) Microbial Ecology of the Gastrointestinal Tract. Annu Rev Microbiol 31:107-33. [3] Charbonneau MR et al (2016) A microbial perspective of human developmental biology. Nature 535:48-55.

13. We have co-evolved with countless species for a very long time, even before our species took on its present form. We and the species with which we co-evolved and now live constitute a holobiont (or superorganism/supraorganism [1]). This is a set of ecosystems that is incredibly complex in terms of both the number of species and the balanced tangle of countless interactions. A random modification of any complex system (e.g., machines, biological organisms, ecosystems …) is a likely cause of dysfunction. [1] Glendinning L, Free A (2014) Supra-organismal interactions in the human intestine. Front Cell Infect Microbiol 4:47. [2] Libertini G (1983) Ragionamenti Evoluzionistici. Società Editrice Napoletana, Naples (Italy). English Edition (2011): Evolutionary Arguments. Azinet Press, Crownsville (USA).

14. Our microbiome has changed enormously from that of primitive people. For example, comparing the microbiome of individuals of the Hadza people (Tanzania) with those of a modern lifestyle population (Italy) the great wealth of the microbiome of the Hadza and the extreme impoverishment of the modern population is evident [1]. These are not considered sick individuals and this is the common condition of our ravaged gut! [1] Schnorr SL (2015) The diverse microbiome of the hunter-gatherer. Nature 518:S14-5.

15. The disaster of the ecosystem existing in our gut is comparable to that of the destruction occurring in vast areas of the Amazon. The virgin Amazon forest. A deforested area. As regards the Amazon forest, we are aware of a huge ecological disaster taking place. As regards what has happened and is happening in our bodies, we have no awareness of the seriousness of the situation.

16. The alterations of our holobiont are not limited to the intestinal ecosystem or to immune system pathologies. There are various diseases caused by alterations of our local ecosystems, generally due to the use of antibacterial substances (antibiotics, soaps, shampoos, etc.). Submammary and axillary mycosis Seborrhoeic dermatitis and dandruff Hidradenitis suppurativa Perineal candidiasis Mycosis of the tongue Intertrigo by Candida Pityriasis versicolor Obesity [1] Chorioamnionitis and spontaneous preterm birth [2], etc. [1] Turnbaugh PJ et al (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027-31. [2] Charbonneau MR et al. (2016) A microbial perspective of human developmental biology. Nature 535:48-55.

17. The alterations of the ecosystems of our holobiont begin from the birth. The microbiome of human infants derives from mother’s faecal, vaginal and skin microbiomes [1]. Childbirth under aseptic conditions or by Caesarean section hinders the normal colonization of the germ-free bowel of the newborn baby and this is a cause of serious diseases [2]. However, the internal and external ecosystems of both the mother and the infant is seriously and continuously altered, before and after birth, by the use of antibiotics and bactericidal substances for topical use [2]. [1] Palmer C et al (2007) Development of the human infant intestinal microbiota. PLoS Biol 5:e177. [2] Blaser MJ (2014) Missing microbes. Oneworld Book, London.

18. After birth, the newborn baby is often separated from his mother and taken in a nursery where his ecosystems are abnormally colonized. Breastfeeding is also often missed out on because of this separation. Over the following years the child's health is “defended” by repeated antibiotic treatments. In developed countries, an average child undergoes 10-12 courses of antibiotics before he is 18 years old [1]. This is absurd and harmful to health. Exposure to microbes in physiological forms is essential for the proper development of the infant [2]. There is extraordinary proof of the utility of some bacteria. There are special human milk oligosaccharides (HMOs) that may be metabolized by specific bacteria and not by the newborn baby. In the mother’s milk, there are roughly 100 different types of these substances [3, 4]. Therefore, through her milk, a mother feeds specific types of bacteria that must be in some way useful to the newborn baby, otherwise their existence would not be justifiable in evolutionary terms. [1] Sharland M (2007) The use of antibacterials in children: a report of the Specialist Advisory Committee on Antimicrobial Resistance (SACAR) Paediatric Subgroup. J Antimicrob Chemoth 60(S1): i15-i26. [2] Charbonneau MR et al. (2016) A microbial perspective of human developmental biology. Nature 535:48-55. [3] Wu S et al (2010). Development of an annotated library of neutral human milk oligosaccharides. J Proteome Res 9:4138-50. [4] Wu S et al (2011) Annotation and structural analysis of sialylated human milk oligosaccharides. J Proteome Res 10:856-68.

19. In our holobiont, countless equilibria occur that are really dangerous to modify! “The indigenous human microbiota is essential to the health of the host.” [1] Antibiotics cause havoc in our ecosystems! For example: “The effect of [two courses of] ciprofloxacin on the gut microbiota was profound and rapid, with a loss of diversity and a shift in community composition occurring within 3-4 days of drug initiation. By 1 week after the end of each course, communities began to return to their initial state, but the return was often incomplete.” [1] In the early twentieth century, Helicobacter pylori was found in the stomachs of almost all people. Now, because of the massive antibiotic use, it is found in less than 6% of children in the USA, Sweden and Germany [2]. People with the bacterium show a greater incidence of stomach cancer while people without the bacterium are more likely to develop asthma, hay fever and skin allergies in childhood [3]. As H. pylori has disappeared from people’s stomachs, there has been an increase in gastroesophageal reflux, and its correlated diseases such as Barrett’s esophagus and esophageal cancer [2]. In primitive people (without antibiotics and with worms!) these problems are non-existent. [1] Dethlefsen L, Relman DA (2011) Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.Proc Natl Acad Sci USA 108(S1):4554-61. [2] Blaser M (2011) Stop the killing of beneficial bacteria. Nature 476:393-4. [3] Chen Y, Blaser M (2007) Inverse associations of Helicobacter pylori with asthma and allergy. Arch Intern Med 167:821-7.

20. Intestinal worms are generally seen as unacceptable parasites. Their eradication is the rule in medical practice and is requested by patients. However, this alters an ancestral balance and causes serious or even life-threatening diseases for patients in which worms are eradicated. Helminthic infection is a sound explanation for the low incidence of autoimmune diseases and allergies in less developed countries, while the same diseases show an increased incidence in industrialized countries [1-4]. “Epidemiological studies suggest that autoimmune diseases, such as multiple sclerosis (MS), are less frequent in individuals who are helminth carriers. This observation has been tested in murine models of colitis, MS, type 1 diabetes and asthma. In each case, mice colonized with helminths show protection from disease.” [5] [1] Leonardi-Bee J et al. (2006) Asthma and current intestinal parasite infection. Systematic review and meta-analysis. Am J Respir Crit Care Med 174:514-23. [2] Zaccone P et al (2006) Parasitic worms and inflammatory diseases. Parasite Immunol 28:515–23. [3] Pugliatti M et al (2002) The worldwide prevalence of multiple sclerosis. Clin Neurol Neurosurg 104:182-91. [4] Weinstock JV et al (2004) Helminths and harmony. Gut 53:7–9. [5] Correale J (2014). Helminth/Parasite Treatment of Multiple Sclerosis. Curr Treat Options Neurol 16:296.

21. Helminthic therapy is the treatment of autoimmune diseases and other immune disorders by deliberate infestation with a helminth or its ova. Current experimental research targets are: multiple sclerosis, ulcerative colitis, inflammatory bowel disease, Crohn’s disease and allergic asthma [1-3]. Helminth presence restrains immune defenses and prevents allergic and autoimmune diseases. Some worms used in helminthic therapy: Necator americanus Trichuris suis Himenoleps diminuta (scolex) [1] Finlay CM et al (2014) Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol Rev 259:206-30. [2] Fleming J et al (2011) Probiotic helminth administration in relapsing–remitting multiple sclerosis: a phase 1 study. Mult Scler 17:743-54. [3] Broadhurst MJ et al (2010) IL-22+ CD4+ T cells are associated with therapeutic trichuris trichiura infection in an ulcerative colitis patient. Sci Transl Med 2:60ra88.

22. Part of the immune disorders arises from other factors. For example, some allergies are caused by the exposure to countless artificially synthesized chemical substances [1], which is another large set of modifications of our ecological niche. However, most of the autoimmune and allergic diseases have a better explanation in the Hygiene Hypothesis [2], namely that the abnormal reduced exposure to antigenic stimuli to which our species is adapted determines an abnormal development of the immune system. This causes pathological immunological reactions against foreign substances which are normally present in the environment (pollen, food, etc.) or against our bodily antigens [3]. Alterations of T helper 1 cells Autoimmune diseases Altered microbiomes Altered contacts with antigens Alterations of T helper 2 cells Allergic diseases Helmint eradication Altered holobiont Alterations in development and other functions Countless new chemical substances Other diseases Chemical alterations [1] Kirchner DB (2002) The spectrum of allergic disease in the chemical industry. Int Arch Occup Environ Health 75:S107-12. [2] Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299:1259–60. [3] Velasquez-Manoff M (2012) An epidemic of absence. Scribner, New York.

23. Medical care for allergies and autoimmune diseases seeks to curb the abnormal immunological reactions by means of antihistamines, corticosteroids, immunosuppressants, monoclonal antibodies and to counter their negative effects on body functions. These treatments act on pathogenic mechanisms and effects of immunological disorders, but cannot erase or limit the primary causes, namely the serious and multiple alterations of our holobiont. As long as we do not act on these primary causes, allergic and autoimmune diseases will continue to cause suffering and even death of hundreds of millions of people. Alterations of our holobiont Allergic and autoimmune diseases, other diseases Sufferings, death Changes in our ecological niche Chemical alterations Evolutionary Medicine Traditional Medicine

24. Conclusion For traditional medicine, each bacterium, virus, fungus, worm or even any contact with another organism is, to a greater or lesser extent, a danger which must be eliminated, limited or, at most, tolerated if clearly not dangerous. For Evolutionary Medicine each of us is a complex set of ecosystems, of which bacteria, viruses, fungi, worms and contacts with other species constitute an integral part. These ecosystems, defined on the whole as a holobiont, are the result of a coevolution that is more ancient than the origin of our species. Any modification of these ecosystems is a potential alteration, i.e., a source of disease or even death. Currently these ecosystems are being continuously and severely altered. This madness is the primary cause of the spread of entire groups of diseases, in particular allergies and autoimmune diseases, which are rare or unknown in primitive populations. An elephant in the glassworks: This is how we might define modern lifestyles and current medicine in terms of our holobiont! to be continued …

25. Conclusion (continued) Of course, we cannot go back to primitive life conditions. But the changes made to the primeval lifestyle to which we are adapted and the alterations of our holobiont must be carefully studied and corrected in the manner and using the measures that are possible and useful. The first step is to understand the problem. Unfortunately, today's medicine has no knowledge of evolutionary mechanisms and has no awareness of the fact that each individual is a complex set of ecosystems. At the same time, evolutionary biologists do not seem to be aware of the fact that the major changes in ecosystems do not take place in distant lands or seas but in our bodies and that this has, for decades, been causing untold suffering and deaths. We might say that ignorance is neither a fault nor a sin. But how many millions of people still have to suffer and die before we all have full awareness of what is happening?

26. Thanks for your attention This oral presentation is also available on my personal pages: www.r-site.org/ageing and you may find it on www.researchgate.net and www.academia.edu (e-mail: giacinto.libertini@tin.it)