The document discusses definitions of biological aging and some of the challenges with defining such a complex process. It explores the concept of biological aging versus "agings" to acknowledge that aging likely involves multiple interconnected processes occurring at different rates. The document also examines issues around causation in aging, discussing the ladder of causation and whether time itself can be considered a causal agent of aging. It questions where the field of biogerontology may lead as our understanding increases and more processes are discovered to be involved in aging.

1. Aging vs agings: limits and
consequences of biomedical
definitions
Attila Csordas
Open Lifespan
openlifespan.org
Cambridge, UK
2019/10/25
Eötvös Loránd University
Budapest
Joint
Theorethical Philosophy &
Logic and Philosophy of
Mathematics
Staff & PhD Seminar

2. Tendency and Outline
I. Introduction
III. philosophy of
biogerontology
II. state-of-the-art
biogerontology
V. political
philosophy
Tehát vagy tiszta science
+ free standing (filtört. nélküli) analízis,
vagy pedig humán megközelítés
- a kettő rosszul vegyül!!!
Barátsággal,
Bence
IV. philosophy of
technology

3. Introduction

4. Old people are pioneers operating
at the limits of lifespan
like a traveling wave
forming the wavefront of the living

5. Chronological age is single biggest risk factor
for the biggest killer diseases

6. global increase in mean life expectancy
2000-15: 5 years with 4.6 years as healthy
longevity
‘An average 16–20% of life is now spent in
late-life morbidity’ ~ Decades of late-life is
now spent fighting age-associated
diseases, compromising human life and life
plans.
64 95 122
healthspan
US, 2017
80% 65+ 1 chronic
68% 65+ 2+ chronic
lifespan longevity

7. 64 95 122
healthspan lifespan longevity
Longevity industry & regulation
billions of dollars invested
ICD/FDA: can aging be classified as a disease???
TAME trial starts this November

8. stem cell
exhaustion
psycho-
logical
individual
biological
aging
chronological
aging
other aging
concepts
population aging
(life expectancy
modal age of death …)
econo-
mical
medical
consequences
mito
dysfunction
senescent
cells
loss of
proteostasis
social
?
cancer
cardio-
vascular
neuro-
degene-
rative
?
?
?
Agings #1
version 0.1

9. Framing Issues
aging is living, living is aging
‘healthy aging’

10. I. biogerontology: state-of-the-art
and a bit of a bleeding edge

11. Biology 101: biological macromolecules

12. Biology 101:
general
molecular
information
flow

13. The fundamental difference (double-task) and the
centrality of time: chronological and biological aging
chronological aging
biological
aging
position(t) -> velocity
velocity(t) -> acceleration

14. 20th
century
chaos
theory vs
data

15. Damage view
2002, SENS
Aubrey de Grey
Cambridge
UK
Intracellular
junk
Cancerous
cells
Cancerous
cells
Intracellular
junk
Extracellular
junk
Cell loss
Death-resistant
cells
Extracellular
links
Mitochondrial
mutations

16. Process centric
view
‘Hallmarks’
2013
Intracellular
junk
Cancerous
cells
Cancerous
cells
Intracellular
junk
Extracellular
junk
Cell loss
Death-resistant
cells
Extracellular
links
Mitochondrial
mutations
The Hallmarks of Aging, Lopez-Otin et al, 2013, Cell

17. 1. Genomic
instability
2. Telomere
attrition
3. Epigenetic
alterations

18. 4. Proteome maintenance, proteostasis

19. 5. Deregulated
nutrient sensing
6. Mitochondrial
dysfunction

20. 7. Cellular
senescence
8. Stem cell
exhaustion
9. Altered intercellular
communication

21. 3 criteria for a hallmark
(1) it should manifest during normal aging
(2) its experimental aggravation should accelerate aging
(3) its experimental amelioration should delay the normal
aging process and hence increase healthy lifespan
most studies in model organisms:

22. ‘Because the hallmarks co-occur during aging and are interconnected, understanding
their exact causal network is an exciting challenge for future work.’
compensatory
multiple damages

23. The Hallmarks of Aging, Lopez-Otin et al, 2013, Cell
Clocks/markers/patterns
telomere clock
epigenetic clock
rest o’ clock #5
rest o’ clock #6
rest o’ clock #4
rest o’ clock #3
rest o’ clock #2 rest o’ clock #1

24. Multiple clocks, markers measure different aging processes
in order to capture broad
spectrum aging (agings) ->
need to split spectrum &
measure lots of things

25. The Epigenetics Aging Clock

26. Missing hallmark processes?

27. Hallmarks of aging, Cell, 2013
PMID: 23746838
What is the ‘ultimate’ problem?
comprehensive
rejuvenation

28. We are all leaves on a tree

29. Single-cell methods can
reconstruct cell trees

30. Aging Cell Trees
Image: Shutterstock

31. Cell Trees as central aging
structure/dynamics
Biological intuition
Mathematical
Evolutionary
Temporality
Spatiality
Originality
Scalability
Comprehensiveness
Biomedical expressive power
Life history

32. Central problem of
comprehensive rejuvenation
Find an algorithm
to restore the
balance and
maintain the
healthy dynamics
of the aging cell
lineage tree.

33. Central Medical Tool
bone marrow
transplantation
cancer
image: foxchase.org
cell therapy
tissue engineering
comprehensive regenerative medicine
informing both diagnosis/treatment

34. Argument
1. Limiting challenge of aging/longevity is comprehensive rejuvenation.
2. Cell lineage tree is the central concept/structure/ and cell tree
dynamics is the central process of (understanding) biological aging(s).
3. Central problem of comprehensive rejuvenation is to find an
algorithm to restore the balance and maintain the healthy dynamics of
the aging cell tree.
4. Indidivual cell trees are needed as the central medical paradigm for
most comprehensive solution counteracting biological aging(s),
developing new diagnosis and treatment options.

35. The plan
Here’s what Aubrey says about the proposal:
'I just wanted to back this up. Let me say that Attila's essential concept in the
document is that we should be able to derive better aging clocks (and we all
know how useful that would be) if we incorporate information about the
phylogenetic distance (in cell-division terms) between individual cells in our
sample, rather than just treating all cells as equivalent and mutually
equidistant.'
simple and beautiful … it must be true
pilot study: Sample Cell Trees to find Human
Aging Biomarkers, detailed proposal, set up
team, academic collaborators

36. II. philosophy of biogerontology
II/a Biological aging definitions and
some problems

37. Definitions
compare: cancer is uncontrolled division of abnormal cells
Small-cell carcinoma
cancer vs cancers (progress)
Diabetes 2 types -> 5 types
(cluster 5: mild age-related, most common form 39-47%)
real/nominal, lexical, stipulative, extensional, intensional, ostensive
what kind of ‘essence’
a collection of definitions, look for
probabilistic talk
causative vocabulary
clinical talk
normativity?
scope/complexity
actionability
why the need to define ‘one’ such phenomenon as biological aging?
definitions appreciative of our limited understanding of aging
acknowledging the ‘known unknowns’ and ‘unknown unknowns’

38. What type of definition are we looking for?

39. biologist definition
scope/
complexity
actionability
Peter Medawar (1952) a loss in organismal fecundity and/or increase in mortality with age low low
Alex Comfort (1979)
decrease in viability and an increase in vulnerability” and “an
increasing probability of death with increasing chronological age” low low
João Pedro de
Magalhães (~2012)
a complex process composed of several features: 1) an exponential
increase in mortality with age; 2) physiological changes that
typically lead to a functional decline with age; 3) increased
susceptibility to certain diseases with age. So, I define aging as a
progressive deterioration of physiological function, an intrinsic age-
related process of loss of viability and increase in vulnerability.
medium low
Carlos López-Otín,
Maria Blasco, Linda
Partridge, Manuel
Serrano, Guido
Kroemer (2013)
Aging is characterized by a progressive loss of physiological
integrity, leading to impaired function and increased vulnerability
to death.
medium low
Aubrey de Grey (2017)
Aging is the result of the burden of decades of unreported damage
to the cellular and molecular structures that make up the
functional units of our tissues. As each essential microscopic
sturcture fails, tissue function becomes progressively compromised
- imperceptibly at first, but ending in the slide into the diseases
and disabilities of aging.
medium/high high
Attila Csordas (2017)
Aging is agings underneath, the result of multiple, diverse and
separate processes, eventually compromising normal functions of
the organism at all levels and at different rates.
medium high

40. Why the need to simplify?
Hallmarks view: why is it not enough of a definition, why there is a need
for a shorthand?
are these all neccessary to define something as biological aging or
sufficient conditions, each?

41. The problem with expressing biological age
as a pseudo-chronological age
desire to simplify in the clinics: vo2max
desire to simplify in science and philosophy
Problem #1: selecting for best predictors of chronological age
might actively select against best predictors of accelerated/
deccelerated biological age
Problem #2: Aging vs aging(s): can such a complex process be
represented with one aggregate number? Isn’t
oversimplification will hide the outlier processes? Isn’t this
hubris as we know too little?
Problem #3: Counterfactual: suppose we break longevity
barrier, can we extrapolate saying 130 yo has a biological age
of a 115 yo?
age is not just a number
X

42. II/b Causation
II. philosophy of biogerontology

43. The ladder of causation in aging
causation and/or explanation
time as a causative agent
root causes of aging, hallmarks
chronological age as
single biggest risk factor
of most chronic diseases

44. The ladder of causation (Pearl)
p(B|A)
probability
can be
expressed in
all levels

45. The rabbit hole of temporal causation
what is the explanatory
power of this type of
causation?
time as a causative agent
aging happens with age
age triggers aging
Morgan Levine
what can physicists say about this
that can inform biogerontology?
quantum
biology
really ???

46. Hallmarks as root causes:
No causation without intervention
RCT logic
(1) it should manifest during normal
aging CONTROL/CORRELATION
(2) its experimental aggravation should
accelerate aging INTERVENTION 1
(3) its experimental amelioration should
delay the normal aging process and
hence increase healthy lifespan
INTERVENTION 2

47. Time Manipulation via Counterfactuals
inexpressible in causal inference models?
time travel

48. Can we die of old age?
Nobody dies directly due to biological aging. Accumulating biological
aging processes are the distal but not the proximate causes of
mortality and death.
Diseases are the proximal causes of death in case of aging associated
increasing mortality.
Eg people die directly due to cardiovascular diseases (heart attack ,
stroke).
proximate causes are a form of sufficient causes
explanation prefer sufficient causes, more common
aging processes are not necessary for death

49. Necessary and sufficient causes
modulate each other
Death
Death
A: A firing bullet B: B firing bullet
A: A firing bullet B: B firing bullet
PS(A)=1 PS(B)=1
both sufficient,
none of them necessary
PN(A)=PN(B)=0
PS(A)<1 PS(B)<1
PN(A) depends on PS(B)
if PS(B)<1 then PN(A)
is necessary,
prisoner would be alive
had A not shot

50. II. philosophy of biogerontology
II/c Where is it going to end?

51. Biogerontology/geroscience is just taking off
1.5% of all genes already,
we don’t know where it’s going to end except theoretical limits
what is the smallest set of interacting genes and gene products where it makes
sense to call it a singular process deserving a unique name?

52. Aging is Living: the holistic camp
development and aging are the same trajectory, conceptually
inseparable
every gene will be involved and eventually those who say aging
is living will be literally true in a complexity/holistic sense

53. Aging vs agings
no new hallmark processes emerge
all the processes are so strongly interconnected we just do not
know it yet, so there will be a quantitative language and
calculus able to grab it all at once and compute (Cell Tree
approach)

54. Recursive definitions
elements of a set are defined with the help of other elements within same set
Peter Aczel, 1977 "An introduction to inductive definitions”
set example: N of natural numbers
(1) 1 is in N.
(2) If an element n is in N then n + 1 is in N.
(3) N is the intersection of all sets satisfying (1) and (2)
function example: f(n+1) is defined via f(n), factorial function n!
(1) 0! = 1.
(2) (n + 1)! = (n + 1)·n!.
non-circular, recursive definitions: there is a base case
- definiens for other elements
- satisfies definition without being defined by it
- terminates recursion, stops infinite regress
thx https://en.wikipedia.org/wiki/Recursive_definition

55. ‘Aging vs agings’ vs ‘aging is agings’
Recursive, inductive definition:
‘Aging is agings underneath, the result of multiple, diverse and separate
processes, eventually compromising normal functions of the organism at all levels
and at different rates.’
4 base cases
all of them
seem sufficient
non-circular: bases cases do not refer to themselves and are primitives
(primary)
composite, other, non-base case elements refer to base cases or other
composite elements, but do not refer to themselves

56. Problems with recursive def
formal issues: multiple base cases
Fibonacci series, 2 base cases: n=0 and n=1
is this enough to well-order these processes?
sufficient vs necessary
content issues: primary hallmark list exhaustive?
mitochondrial stress can lead to senescence

57. III. philosophy of technology
health disease
aging

58. Health concepts
health is the lack of diagnosable disease
The naturalist conception of disease (Boorse 1975,1997) is that the
human body comprises organ systems that have natural functions from
which they can depart in many ways. Some of these departures from
normal functioning are harmless or beneficial, but others are not. The
latter are ‘diseases’. disease: i., abnormal functioning of some bodily
system and ii., a judgment that the resulting abnormality is a bad one.
vs constructivism

59. Conceptual twins, separated at
birth
biological life
lifespan/longevityhealth
there’s only health when there’s a quantity of
life and there’s only a quantity of life when
there’s a a threshold, viable amount of health
present.
which is a more fundamental concept? 2 approaches
health
lifespan
life

60. Can you imagine a world without disease but
with biological aging? Neither can I
1. Imagine a PW1 where human (medical) technology eliminated all diseases but
where people would still go through biological aging. Can we succeed in imagining
such a world?
2. In PW1 people would not die of diseases, either infectious or non-infectious
conditions. In this world people would die of external, non-infectious reasons, outside
the domain of medically diagnosable pathologies.
3. people still undergo biological aging, so they still experience functional decline and
increased mortality with age due to biological aging.
4. But increased mortality means people would still die from medical consequences of
aging.
5. Nobody dies directly due to biological aging. distal, not proximal.
6. Diseases are the proximal causes of death in case of aging associated increasing
mortality. 7. Contradiction in imagining such a world as our main stipulation was that
all diseases have been prevented or cured, yet we still need to assume that diseases
are killing people due to our other assumption of this world, namely that biological
aging still continues to happen.
8. Conclusion: we cannot conceptually separate diseases and biological aging from
each other. Although biological aging is not classified currently as a disease it clearly
leads to the accumulation of age-associated diseases.
9. Counteracting biological aging cannot be considered an enhancement but a therapy
or prevention.

61. philosophy of technology
the enhancement debate

62. Different accounts of
enhancement/treatment
enhancement goes further than normal functionings
vaccines prevent, stimulating our immune system
social resistance
professional domain account
normal function account
disease based account
context:
proper goals of medicine
proper goals of society

63. Superpower enhancement test
not for boasting, nothing idiosyncratic, not for demonstrative purposes

64. Superpower enhancement test
they confer competitive benefits, pro-inequality, unlike longer life

65. Longer life is not an enhancement as the
dead don’t compete
goals of society context
Hypothetical job interview in an Open Lifespan world
A: 200 year old
B: 38 yo (10+ years of experience)
C: don’t know age but took cognitive enhancer others don’t
know about
same amount of time to prepare for the interview

66. Ethics: The Nagel principle
life’s default positivity
1. It is good simply to be alive.
2. It’s better to be alive than dead.
3. Life is a default positivity.
4. Experiencing life is a default positivity.
5. Life is a default value.
6. Living (experienced life) is valuable by default or in itself.
7. The balance is always positive when it comes to life.
8. Life is an essential quality we all have.

67. IV. political philosophy of longevity
Open Lifespan

68. What is the ‘ultimate’ project?
Closed Lifespan
Our current share
‘An average 16–
20% of life
is now spent in
late-life
morbidity’
Possible

69. What is the ‘ultimate’ project?
Closed Lifespan
Our current share
‘An average 16–
20% of life
is now spent in
late-life
morbidity’
Possible
Impossible
overestimate
immortality
immortals
death defying
infinity
living forever
forever young
perpetual

70. What is the ‘ultimate’ project?
Closed Lifespan
Our current share
immortality
immortals
death defying
infinity
living forever
forever young
perpetual
‘An average 16–
20% of life
is now spent in
late-life
morbidity’
Possible
Impossible
overestimateunderestimate

71. What is the ‘ultimate’ project?
Closed Lifespan
Our current share
‘An average 16–
20% of life
is now spent in
late-life
morbidity’
overestimateunderestimate
Possible
Impossible
Open Lifespan
breaking maximum
longevity barrier
fixed low
mortality
comprehensive
rejuvenation
immortality
immortals
death defying
infinity
living forever
forever young
perpetual

72. Open Lifespan, Open Healthspan
what is the theoretical, reachable maximum?
what is as long as possible?
Open Life is a possible world, where people can choose Open
Lifespan, an open-ended, indefinitely long healthy lifespan. Open
Lifespan is achieved via Open Healthspan Technologies developed
and accessible enough that all people can choose to go through
continuous interventions to counteract the biological aging
process and have a fixed, small but nonzero mortality rate due to
external causes of death.
not utopian, only one parameter is changed

73. Open
Life
Actual
World
Less
Probable Worlds
Highly
Probable Worlds
Limiting
Possible Worlds
current
thinking

74. Open
Life
Actual
World
Less
Probable Worlds
Limiting
Possible Worlds
Highly
Probable Worlds
Increasing
Life Expectancy
Closed Lifespan
Breaking Maximum
Closed Lifespan
Barrier
Open Lifespan
Open
Lifespan
thinking

75. What is it like to be 572 year old while
healthy?
Distant future self-simulation

76. Why political philosophy?
normative behaviourism:
insurgence
crime
SLDs are best
health/longevity as political priorities

77. Arguments for
more democratic
more liberal
more egalitarian
more diverse
less ageist

78. Ongoing projects
aging/longevity
climate change AI
centreleft right

79. Conclusion: philosophy of biogerontology/geroscience have
distinct conceptual problems amenable to philosophical
enquiry
Conclusion: biological aging might be defined with a recursive
definition using the hallmark process based framework.
Conclusion: this is an actionable, dynamic definition
Thanks!
A “rendszer” után a filozófia többé nem támaszthat
igényt a pozitív tudás rangjára, csak egy
tudásszintünkkel összhangban levő, teoretizált
“fogalmi elbeszélés” lehet, amely - szándékai szerint -
általánosan orientáló, megvilágosító.