ontology of aging barry smith march 17, 2015 1

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Ontology of Aging

Barry Smithhttp://ontology.buffalo.edu/smith

March 17, 2015

http://ontology.buffalo.edu/smith

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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.”

http://www.sens.org/ 3

http://bigthink.com/ideafeed/aging-is-a-disease-lets-cure-it4

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What is a disease?

What is a disease?

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

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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

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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)

Definitions of Disease in terms of dysfunctionA 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

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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’?

Ontology for General Medical Science (OGMS)

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PMC3041577

The Very Top (BFO)

continuant process

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The Very Top

continuant

organism attributeof an

organism

process

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The Very Top

continuant

independent continuant

dependent continuant

process

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The Very Top

continuant

independent continuant

dependent continuant

process

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quality

temperature

independentcontinuant

dependentcontinuant

quality

temperature types

instances

organism

John John’s

temperature

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dependentcontinuant

quality

temperature

organism

John John’s

temperature

occurrent

process

course of temperature

changes

John’s temperature history

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A Chart representing how John’s temperature

changes over time

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temperature

John’s temperature

37ºC 37.1ºC 37.2ºC 37.3ºC

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

continuants occurrents

course of John’s temperature


has_participant

coronary heart disease

John’s coronary heart disease

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asymptomatic (‘silent’) infarction

early lesions and small

fibrous plaques

stable angina

surface disruption of plaque

unstable angina

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

time


dependentcontinuant

quality

temperature

organism

John John’s

temperature

occurrent

process


changes

John’s temperature history

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dependentcontinuant

?

diseaseorganism

John John’s

cardiovasculardisease

occurrent

process

disease course

course of John’s cardiovascular

disease 23

The Very Top

continuant occurrent


dependentcontinuant

quality disposition

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Disposition

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

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dependentcontinuant

disposition

to ripen

disposition of this fruit: to ripen

occurrent

process

ripening

process of ripening in this fruit

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Disositions are realized in processes


dependentcontinuant

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

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Function

continuantoccurrent


dependentcontinuant

quality disposition

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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

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dependentcontinuant

function

to seeeye

John’s eye function of John’s eye: to see

occurrent

process

process of seeing

John’s seeing

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dependentcontinuant

function

to see

function of John’s eye: to see

occurrent

process

functioning = realization of function in

a process of seeing

John’s seeing31

Functions are realized in functionings

:.

There are no such things as biological dysfunctions

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Only (body parts with) functions survive evolutionary selection

:.

There are no such things as biological dysfunctions

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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

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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: baldness36

:.

Every disease needs a disorder

– independent continuant (physical part of the extended organism)

A causally linked combination of physical components that is clinically abnormal

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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

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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.

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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)

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healthy functioning

functioning above threshold of clinical abnormality

dysfunctioning characteristic of disease

disease disposition to dysfunctioning

not function-ing at all


dependentcontinuant

disposition

diseasedisorder

John’s disordered

heart

John’s coronary heart

disease

occurrent

process

course of disease

course of John’s disease

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• A disease is not a process• Aging is a process• Therefore aging is not a disease

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A (too) simple argument


dependentcontinuant

disposition

disease: progeria

disorder

John’s disordered

body

John’s progeria

occurrent

process

premature aging

John’s premature aging

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Hutchinson–Gilford progeria syndrome


dependentcontinuant

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

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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


dependentcontinuant

disposition

disposition: to get older

organism

JohnJohn’s disposition

to get older (= to stay alive)

occurrent

process

age increasing at the rate of 1 second per

second

John’s getting older

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Carlos Lopez-Otin, et al., “The Hallmarks of Aging”, Cell 153, 2013

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compare: Landmarks for pregnancy, landmarks menopause, …

What determines the landmark age for ‘normal

aging’

What does ‘normal’ mean?

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For anatomy we have an answer to this question

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Foundational Model of Anatomy

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Canonically (normally) human beings have 32 teeth• This is part of the Bauplan of human beings • US adults have an average of 24.92 teeth• Thus ‘normal’ ‘statistically normal’

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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

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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 …) -

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Life plan (human, first 9 days)

proposal

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

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

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Canonical whole (human) organism stages

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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

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post-natal development stage

life of whole human

aging stage

reproductive stage

maturation stage

growth stage

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post-natal stages (women)

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life of whole human

geripause

reproductive stage

maturation stage

growth stage

menopause

P

post-natal stages (men)

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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?

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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?

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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?

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The grandmother hypothesisgrandmothers allow for more successful reproduction (are selected for)

grandmother whales lead salmon hunting packs and thereby help to keep young male whales alive longer

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some evidence of a post-reproductive stage in nonhuman primates

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

counterintuitive consequences

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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 201272

stages after birth

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life of whole human

healthy aging

reproductive stage

maturation stage

growth stage

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dementia

Two schools of thought when it comes to extending the human lifespan

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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

ontology of aging barry smith march 17, 2015 1

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