Ontology of Aging Barry Smith March 17,

Two schools of thought when it comes to extending the human lifespan 1.incremental approach, eliminate non- communicable diseases like Alzheimer's, diabetes and cancer. 2.treat aging as a disease and try to cure it “One proponent of this latter method is Aubrey de Grey, whose activism includes awarding cash prizes to scientists who succeed at extending the lifespans of mice.” 2

3

4

What is a disease? 5

MeSH: A definite pathologic process with a characteristic set of signs and symptoms. 6

Problems with a view of a disease as a process two otherwise identical individuals may have the same disease yet manifest very different disease processes if you have a disease, then you have it from the very start of when you have it, before any disease process begins Need to distinguish Disease vs. disease course 7

What is a disease? World Health Organisation A disease is: an interconnected set of one or more dysfunctions in one or more body systems including: a pattern of signs, symptoms and findings (symptomatology - manifestations) a pattern or patterns of development over time (course and outcome) a common underlying causal mechanism (etiology) 8

Definitions of Disease in terms of dysfunction A disease is: an interconnected set of one or more dysfunctions in one or more body systems … (WHO) a type of internal state which is an impairment of normal functional ability (Boorse) a harmful deviation from the normal structural or functional state of an organism (Encyclopedia Britannica) what is a dysfunction? 9

disease = a harmful deviation from the normal structural or functional state of an organism not any deviation is a disease (running a marathon, fainting when someone insults you) the deviation has to be rooted in some bodily change not every harmful deviation is a disease (losing milk teeth, menopause …) the harm has to be outside the normal life plan what is a ‘structural or functional state’? 10

Ontology for General Medical Science (OGMS) 11 PMC

The Very Top (BFO) continuantprocess 12

The Very Top continuant organism attribute of an organism process 13

The Very Top continuant independent continuant dependent continuant process 14

The Very Top continuant independent continuant dependent continuant process 15 quality temperature

independent continuant dependent continuant quality temperature types instances organism John John’s temperature 16

independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process course of temperature changes John’s temperature history 17

A Chart representing how John’s temperature changes over time 18

temperature the temperature of the top (exists continuously through time) 37°C temperature quality 38°C temperature quality 39°C temperature quality 40°C temperature quality 41°C temperature quality instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 in nature, no sharp boundaries here

temperature John’s temperature 37ºC37.1ºC37.2ºC37.3ºC instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 continuants occurrents course of John’s temperature course of temperature has_participant

coronary heart disease John’s coronary heart disease 21 asymptomatic (‘silent’) infarction early lesions and small fibrous plaques stable angina surface disruption of plaque unstable angina instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 time

independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process course of temperature changes John’s temperature history 22

independent continuant dependent continuant ? disease organism John John’s cardiovascular disease occurrent process disease course course of John’s cardiovascular disease 23

The Very Top continuant occurrent independent continuant dependent continuant qualitydisposition 24

Disposition - of a glass vase, to shatter if dropped - of a human, to eat - of a banana, to ripen - of John, to lose hair dispositions are tendencies, potentialities … dispositions must have some physical basis 25

dependent continuant disposition to ripen disposition of this fruit: to ripen occurrent process ripening process of ripening in this fruit 26 Disositions are realized in processes

independent continuant dependent continuant disposition to go bald integu- mentary system John’s integumentary system John’s disposition: to go bald occurrent process process of seeing John’s going bald 27

Function continuant occurrent independent continuant dependent continuant qualitydisposition 28 function

:. Function - of a screwdriver: to transmit torque - of a liver: to store glycogen - of a birth canal: to enable transport - of a eye: to see - of a mitochondrion: to produce ATP functions are dispositions which are designed or selected for functions are realized in functionings 29

independent continuant dependent continuant function to see eye John’s eye function of John’s eye: to see occurrent process process of seeing John’s seeing 30

dependent continuant function to see function of John’s eye: to see occurrent process functioning = realization of function in a process of seeing John’s seeing 31 Functions are realized in functionings

:. There are no such things as biological dysfunctions 32 Only (body parts with) functions survive evolutionary selection

:. There are no such things as biological dysfunctions 33 Only (body parts with) functions survive evolutionary selection But there are dysfunctionings = processes in which functions are realized only partially, or incorrectly, or in which realization fails

Big Picture 34

35 Physical Disorder

Clinically abnormal (1) not part of the life plan for an organism of the relevant type (unlike pregnancy, menopause, …), (2) causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction (some HARM) (3) such that the elevated risk exceeds a certain threshold level.* *Compare: baldness 36

:. Every disease needs a disorder – independent continuant (physical part of the extended organism) A causally linked combination of physical components that is clinically abnormal 37

Pathological Process =def. A bodily process that is a manifestation of a disorder and is clinically abnormal. Disease =def. A disposition to undergo pathological processes that exists in an organism because of one or more disorders in that organism Disease course =def. – The aggregate of processes in which a disease disposition is realized. 38

Huntington’s Disease – genetic (sure-fire) Etiological process - inheritance of >39 CAG repeats in the HTT gene –produces Disorder - chromosome 4 with abnormal mHTT –bears Disposition (disease) - Huntington’s disease –realized_in Pathological process - accumulation of mHTT protein fragments, abnormal transcription regulation, neuronal cell death in striatum –produces Abnormal bodily features –recognized_as Symptoms - anxiety, depression Signs - difficulties in speaking and swallowing 39

Dispositions and Predispositions All diseases are dispositions; not all dispositions are diseases. Predisposition to Disease =def. – A disposition in an organism that constitutes an increased risk of the organism’s subsequently developing some disease. 40

HNPCC - genetic pre-disposition Etiological process - inheritance of a mutant mismatch repair gene –produces Disorder - chromosome 3 with abnormal hMLH1 –bears Disposition - HNPCC –realized_in Pathological process - abnormal repair of DNA mismatches –produces Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2) –bears Disposition (disease) - non-polyposis colon cancer –realized in Symptoms (including pain) 41

42 healthy functioning functioning above threshold of clinical abnormality dysfunctioning characteristic of disease disease  disposition to dysfunctioning not function- ing at all

independent continuant dependent continuant disposition disease disorder John’s disordered heart John’s coronary heart disease occurrent process course of disease course of John’s disease 43

A disease is not a process Aging is a process Therefore aging is not a disease 44 A (too) simple argument

independent continuant dependent continuant disposition disease: progeria disorder John’s disordered body John’s progeria occurrent process premature aging John’s premature aging 45 Hutchinson–Gilford progeria syndrome

independent continuant dependent continuant disposition aging syndrome disorder John’s disordered body John’s aging syndrome occurrent process aging John’s aging = process of realization of John’s aging syndrome 46 if aging were a disease, it would look like this

We focus in what follows on ‘normal aging’? = non-premature aging which is not cut short by early death How is this distinguished from the passage of time in an organism? 47

independent continuant dependent continuant disposition disposition: to get older organism John John’s disposition to get older (= to stay alive) occurrent process age increasing at the rate of 1 second per second John’s getting older 48

Carlos Lopez-Otin, et al., “The Hallmarks of Aging”, Cell 153,

50 compare: Landmarks for pregnancy, landmarks menopause, …

What determines the landmark age for ‘normal aging’ What does ‘normal’ mean? 51

For anatomy we have an answer to this question 52

Foundational Model of Anatomy 53 Canonically (normally) human beings have 32 teeth This is part of the Bauplan of human beings US adults have an average of teeth Thus ‘normal’  ‘statistically normal’

54 represents canonical adult human anatomy = the Bauplan generated by the coordinated expression of the human organism’s own structural genes* *thus there is still a statistical dimension here, but not at the level of patient phenotypes (teeth lost in bar fights) Foundational Model of Anatomy Ontology

Canonically (normally) human beings have 2 lungs This is part of the Bauplan of human beings Canonically (normally) death is the terminal boundary of a process of aging This is part of the life plan of human beings 55

From anatomy to development Canonical Bauplan = no amputation stumps, no effects of steroids, no webbed fingers … Canonical life plan = canonical sequence of life processes for an organism of this species (no early death through injury or famine, no life-changing childhood disease, no excessive studying of philosophy …) - 56

57 Life plan (human, first 9 days)

proposal there is an aging stage that is part of the canonical life plan for human beings 58

What makes premature aging non-normal is that it does not fit in the right way into the life plan for an organism of the relevant type It does not fit into the canonical cycle of stages generated by the coordinated expression of the organism’s own developmental genes 59

Canonical whole (human) organism stages 60 whole human development stage post-natal development stage aging stage reproductive stage maturation stage growth stage P life of whole human pre-natal development stage morula stage embryo stage zygote stage P blastula stage gastrula stage

stages after birth 61 whole human development stage post-natal development stage life of whole human aging stage reproductive stage maturation stage growth stage P

post-natal stages (women) 62 whole human development stage post-natal development stage life of whole human geripause reproductive stage maturation stage growth stage menopause P

63

post-natal stages (men) 64 whole human development stage post-natal development stage life of whole human andropause???? reproductive stage maturation stage growth stage

the argument for an aging stage (stage of ‘natural aging’) aging is programmed by the genome what is programmed for by the genome cannot be a disease therefore aging is not a disease but why would evolution select for a post-reproductive stage? 65

cellular senescence organisms (like us) rely on cell division to survive, the more cell division is programmed for, the greater the risk of uncontrolled cell division hence cell senescence is programmed for, too but if cell senescence occurs too early, you lose reproductive capacity hence there is a programmed cellular senescence overshoot But couldn’t this overshoot be just an epiphenomenon? 66

human females (and killer whales) live many years past the end of reproduction female chimps in the wild don’t why would evolution select for a post- reproductive stage? 67

The grandmother hypothesis grandmothers allow for more successful reproduction (are selected for) grandmother whales lead salmon hunting packs and thereby help to keep young male whales alive longer 68

some evidence of a post-reproductive stage in nonhuman primates 69

70

but the thesis that aging is not a disease because it is programmed for has counterintuitive consequences 71

how can there be ‘typical diseases of old age’ benign prostatic hypertrophy is normal for the age group formed by aged men the central tenet of geriatrics is that senility is a disease: suppose this tenet is false? if we all get senile, it is part of our genetic program, and so not a disease Compare C. Boorse, “Replies to recent critics”, August

73

stages after birth 74 whole human development stage post-natal development stage life of whole human healthy aging reproductive stage maturation stage growth stage P dementia

Two schools of thought when it comes to extending the human lifespan 75 whole human development stage post-natal development stage life of whole human healthy aging reproductive stage maturation stage growth stage P dementia 1.incremental approach, eliminate non- communicable diseases like Alzheimer's, … 2.treat aging as a disease and try to cure it