Ontology of Aging and DeathBarry Smith

http://ontology.buffalo.edu/smith

Presented at the Rostock Symposium on Systems Biology and Bioinformatics in Aging Research, September 20, 2013

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Aging has something to do with time

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applies to both time intervals and processes3

The Allen Interval Calculus

has something to do with death(we need both processes and process boundaries)

Beginning

Ending

Threshold / Meeting point

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for example: Aging and Death

Beginning

Ending

Threshold

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Aging

Death

When does aging begin?Beginning

Ending

Threshold

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Aging

Death

?

When does baldness begin?

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Aging

Death

Processes in the organism

Intervals of time

occupy

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Aging

Death

Process boundaries

Instants of time

occupy

Is death a process or a process boundary?

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Aging

Death

Processes in the Organism

Regions of Time

occupy

Dying

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death in the Gene Ontology

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is death 1. a biological process, or 2. the terminal boundary of a biological process?

A philosophico‐onto‐biological puzzle

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is death 1. a biological process, or 2. the terminal boundary of a biological process?

A philosophico‐bio‐gerontologicalpuzzle

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aging part_of life of organismdeath boundary_of life of organism

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Aging

Death

Life of the Organism

Regions of Time

Conception …

death boundary_of life of organism

every instance of death boundary_of life of some organism? every life of an organism has_boundary some death 

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Metabolism

Death

Life and afterlife of organism

Regions of Time

Abiotic chemistry

aging part_of life of organism

every instance of aging part_of life of some organismNOT: every instance of life of organism has_part aging

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because a life may be cut short by early deathThus also NOT:  death boundary_of process of aging

death may not follow any process of agingNOT:  aging has_boundary death 

premature aging may be followed by a period of rejuvenation

How to define ‘life of organism’?Roughly: The sum total of all processes taking place within the spatiotemporal region occupied by the organism

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How to define ‘life of organism’?Roughly: The sum total of all processes taking place within the spatiotemporal region occupied by the organism

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t1

t3t2

• How to distinguish age-related causes (aging processes) from other causes of death?

• Roughly: age-related causes = processes normally part of the normal aging process

• What does ‘normally’ mean?

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has 83281 types and 3 million relations representing canonical adult human anatomy= the Bauplan generated by the coordinated expression of the organism’s own structural genes.

Canonical anatomy contrasted with variant anatomy and with instantiated anatomy

Canonical ≠ statistically normal

Foundational Model of Anatomy Ontology

Foundational Model of Anatomy (FMA)

Pleural Cavity

Interlobar recess

Mesothelium of Pleura

Pleura(Wall of Sac)

VisceralPleura

Pleural Sac

Parietal Pleura

Anatomical Space

OrganCavity

Serous SacCavity

AnatomicalStructure

Organ

Serous Sac

MediastinalPleura

Tissue

Organ Part

Organ Subdivision

Organ Component

Organ CavitySubdivision

Serous SacCavity

Subdivision

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canonically (normally) human beings have 32 teeth• 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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The GO is a canonical representation

• “The Gene Ontology is a computational representation of the ways in which gene products normally function in the biological realm”

• Nucleic Acids Research. 2006: 34.

Thus the GO is distinguished from a disease ontology and from an ontology of biological processes in vitro 

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The Gene Ontologyrepresents what is normal in the realms of 

• cellular components• molecular functions • biological processes

= roughly, what pertains to ‘wild type’, as opposed to experimentally modified, organisms= what happens when genes, proteins function normally in the development of an organism

What makes aging processes normal aging processesWhat makes a case of premature aging non‐normal?What makes an early death early?Answer: that it does not fit in the right way into the life plan for an organism of this typeIt does not fit into the canonical cycle of stages

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“Reproductive stage” in Bioportal

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How do we represent an organism’s canonical life plan?

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Aging processes

Death

Processes in the organism

Stages

Regions of time

organism senescence stage

organism maturation stage

organism reproductive stage

What makes the ontology of stages so hard?Stages are not simply segments of the life of the organism. Not all processes occurring in the organism in the organism reproductive stage are reproductive processes. BFO: process profilesThere is a progression of stages, but some stages may overlap (e.g. senescent stage and reproductive stage)and not all stages require specific earlier stages in order to exist.Most importantly, cells, organs and other organism parts go through stages too

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GO has a non‐unified treatment of stages (aka phases)

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but it mainly deals with stages through use of ‘developmental’

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developmental pigmentation is a special kind of pigmentationdevelopmental aging is a special (= normal) kind of aging

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GO:0043473 pigmentation

Definition:The deposition or aggregation of coloring matter in an organism, tissue or cell.

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developmental pigmentation

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developmental pigmentation

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pigmentation during development (≠ developmental pigmentation)*

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*although GO asserts the two as synonyms

Where can one find a good ontology of stages?

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In the life cycle of plants we have alternating generations:gametophyte = whole plant in haploid stage; male and female gametes fuse to produce the zygote from which the sporophyte arisessporophyte = whole plant in diploid stage (the dominant form in vascular plants such as ferns); produces spores from which the gametophyte arises.

whole plant development stage

PO:0007033

gametophyte development stage

PO:0028003

sporophyte development stage

PO:0028002

life of whole plantPO:0025337

PP

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whole plant development

stagePO:0007033

gametophyte development

stagePO:0028003

sporophyte development

stagePO:0028002

life of whole plant

PO:0025337

plant spore stage

PO:0025375

gametophyte vegetative stage

PO:0025340

gametophyte dormant stagePO:0025342

gametophyte reproductive

stagePO:0025341

gametophyte senescent stage

PO:0025343

sporophyte senescent

stagePO:0007017

sporophyte dormant stagePO:0007132

sporophyte reproductive

stagePO:0007130

sporophyte vegetative stage

PO:0007134

plant zygote stage

PO:0028002

PP

is_apart_

of

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Plant Stage Ontology (principal whole plant development stages)

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Life cycle of Selaginella apoda (Felsen Moosfarn)

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44http://blog.botanybill.info/?p=1225

sporophyte senescent stagePO:0007017

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GO:0010259: multicellular organismal aging

Definition: An aging process that has as participant a whole multicellular organism. Multicellular organism aging includes loss of functions such as resistance to disease, homeostasis, and fertility, as well as wear and tear. Multicellular organisms aging includes processes like cellular senescence and organ senescence, but is more inclusive.

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GO:0007568: agingDefinition: A developmental process that is a deterioration and loss of function over time. Aging includes loss of functions such as resistance to disease, homeostasis, and fertility, as well as wear and tear. Aging includes cellular senescence, but is more inclusive. May precede death (GO:0016265) and may succeed developmental maturation (GO:0021700).

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GO requires a term for developmental aging

Vascular plant life cycle

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http://www.flickr.com/photos/claytonvnps/8507360783/

http://www.flickr.com/photos/97311348@N07/9778785044/sizes/o/in/photostream/

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honour of Dr. Leonard Hayflick, co-author with Paul Moorhead, of the first paper describing it in 1961. Cells can also be induced to senesce by certain toxins, irradiation, or the activation of certain oncogenes. In response to DNA damage (including shortened telomeres), cells either age or self-destruct (apoptosis, programmed cell death) if the damage cannot be easily repaired. In this 'cellular suicide', the death of one cell, or more, may benefit the organism as a whole. For example, in plants the death of the water-conducting xylem cells (tracheids and vessel elements) allows the cells to function more efficiently and so deliver water to the upper parts of a plant. The ones that do not self-destruct remain until destroyed by outside forces. Though they no longer replicate, senescent cells remain metabolically active and generally adopt phenotypes including flattened cell morphology, altered gene expression and secretion profiles (known as the senescence-associated secretory phenotype) and positive senescence

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The End: Senescence and Cell Death (With Yuan Zhong and Jared Taylor) - Plants, like animals, employ cell death as a normal and necessary part of life. Cell death occurs during developmental processes, including embryo and leaf development, vascular tissue development, and various reproductive processes. Pathogen infection can initiate the hypersensitive response which can include a rapid cell

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age-dependent behavioral declineGO:0035982

synonym (exact): behavioral aging

Definition:A developmental process that arises as an organism progresses toward the end of its lifespan that results in a decline in behavioral activities such as locomotory behavior, and learning or memory.

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GO:0035982: age-dependent

behavioral decline

Summarizing: whole (human) organism stages in GO‐PO style

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whole human development stage

post‐natal development stage

life of whole human

senescent (aging) stage

age‐dependent behavioral decline

stage

reproductive stage

maturation stage

growth stage

P

is_apart_of

P

Acknowledgements

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Gene Ontology (GO)Jane Lomax (EBI)Chris Mungall (Berkeley)

iPlantRamona Walls (University of Arizona)

Plant Ontology (PO)Pankaj Jaswal, Laurel Cooper, Justin Elser(Oregon State University)Dennis W. Stevenson, Ciaran Maloney (New York Botanical Gardens)

Ontology for General Medical Sciences (OGMS)Werner Ceusters (Buffalo)Lindsay Cowell (Texas)Albert Goldfain (Syracuse)Alan Ruttenberg (Buffalo)Richard Scheuermann (J. Craig Venter Institute)