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Aging vs agings: limits and consequences of biomedical definitions

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Talk given by Attila Csordas on a joint Philosophy of Science, Mathematics and Logic PhD Seminar at the Institute of Philosophy at Eötvös University, Budapest, October, 2019
http://phil.elte.hu/tpf/2019-2020/October/

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Aging vs agings: limits and consequences of biomedical definitions

  1. 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. 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. 3. Introduction
  4. 4. Old people are pioneers operating at the limits of lifespan like a traveling wave forming the wavefront of the living
  5. 5. Chronological age is single biggest risk factor for the biggest killer diseases
  6. 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. 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. 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. 9. Framing Issues aging is living, living is aging ‘healthy aging’
  10. 10. I. biogerontology: state-of-the-art and a bit of a bleeding edge
  11. 11. Biology 101: biological macromolecules
  12. 12. Biology 101: general molecular information flow
  13. 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. 14. 20th century chaos theory vs data
  15. 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. 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. 17. 1. Genomic instability 2. Telomere attrition 3. Epigenetic alterations
  18. 18. 4. Proteome maintenance, proteostasis
  19. 19. 5. Deregulated nutrient sensing 6. Mitochondrial dysfunction
  20. 20. 7. Cellular senescence 8. Stem cell exhaustion 9. Altered intercellular communication
  21. 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. 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. 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. 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. 25. The Epigenetics Aging Clock
  26. 26. Missing hallmark processes?
  27. 27. Hallmarks of aging, Cell, 2013 PMID: 23746838 What is the ‘ultimate’ problem? comprehensive rejuvenation
  28. 28. We are all leaves on a tree
  29. 29. Single-cell methods can reconstruct cell trees
  30. 30. Aging Cell Trees Image: Shutterstock
  31. 31. Cell Trees as central aging structure/dynamics Biological intuition Mathematical Evolutionary Temporality Spatiality Originality Scalability Comprehensiveness Biomedical expressive power Life history
  32. 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. 33. Central Medical Tool bone marrow transplantation cancer image: foxchase.org cell therapy tissue engineering comprehensive regenerative medicine informing both diagnosis/treatment
  34. 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. 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. 36. II. philosophy of biogerontology II/a Biological aging definitions and some problems
  37. 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. 38. What type of definition are we looking for?
  39. 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. 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. 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. 42. II/b Causation II. philosophy of biogerontology
  43. 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. 44. The ladder of causation (Pearl) p(B|A) probability can be expressed in all levels
  45. 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. 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. 47. Time Manipulation via Counterfactuals inexpressible in causal inference models? time travel
  48. 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. 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. 50. II. philosophy of biogerontology II/c Where is it going to end?
  51. 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. 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. 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. 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. 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. 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. 57. III. philosophy of technology health disease aging
  58. 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. 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. 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. 61. philosophy of technology the enhancement debate
  62. 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. 63. Superpower enhancement test not for boasting, nothing idiosyncratic, not for demonstrative purposes
  64. 64. Superpower enhancement test they confer competitive benefits, pro-inequality, unlike longer life
  65. 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. 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. 67. IV. political philosophy of longevity Open Lifespan
  68. 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. 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. 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. 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. 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. 73. Open Life Actual World Less Probable Worlds Highly Probable Worlds Limiting Possible Worlds current thinking
  74. 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. 75. What is it like to be 572 year old while healthy? Distant future self-simulation
  76. 76. Why political philosophy? normative behaviourism: insurgence crime SLDs are best health/longevity as political priorities
  77. 77. Arguments for more democratic more liberal more egalitarian more diverse less ageist
  78. 78. Ongoing projects aging/longevity climate change AI centreleft right
  79. 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.

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