Episode: 53 Xenogenesis - Ageing and Immortality Special

XenoThesis

In episode 53 (Special Episode 3), Richard and Michael discuss Ageing and Immortality, from a biological and Ethical prespectives.

Timestamps

00:00:00 - Start
00:31:00 - Intro
00:03:22 - Historical Lifespan Trends [1,2]
00:08:36 - Definitions: Ageing, Immortality
00:11:54 - Aging as increasing risk of death with time [3,4], Negligible senescence [5] constant (low) risk of death
00:13:30 - how immortal is immortal?
00:15:52 - Mortal Individuals, immortal populations
00:17:16 - Individuals are energetically open but informationally closed
00:20:30 - The environment cannot update an individual’s genome
00:21:10 - Individuals are robust populations are antifragile [6]
00:23:20 - T/Memetic feedback on genetic information [7]
00:24:16 - the ‘immortal’ jellyfish? - blurring individual/population boundaries [8]
00:25:40 - Soma Vs Germline [9,10]
00:32:07 - Hurdles to Achieving more robust ageing
00:33:30 - Senescence [11]
00:37:18 - Antagonistic Pleiotropy [12]
00:41:40 - Descriptive frameworks: The Hallmarks of ageing [13, 14]
00:42:26 - primary hallmarks
00:42:30 - Genomic Instability
00:42:48 - Telomeres [15,16]
00:45:10 - Hayflick limit [17]
00:47:30 - DNA Repair and Ageing as signal transmission problem [18,19]
00:50:16 - Game theory of robustness & reproductive speed trade-offs [20]
00:54:51 - DNA fidelity and Repair genes often mutated in progeriod (accelerated ageing) diseases. [21]
00:56:38 - Organisms have similar mutation densities at end of life [22]
00:57:10 - Error Catastrophe theory of ageing [23]
00:58:02 - Cause of Damage Hallmarks, epigenetics
00:59:40 - DNA methylation
01:00:07 - Histone modifications
01:02:40 - Epigenetics and Development
01:03:45 - Digital vs analog computation in biology
01:06:02 - Epigenetic age clocks [24]
01:08:27 - Predicting when you will die
01:14:40 - Integrative hallmarks: Stem Cells
01:18:38 - Waddington’s Epigenetic landscape [25,26]
01:25:24 - Induced Stem cells and cellular reprogramming [27]
01:29:20 - rejuvenation through epigenetic reprogramming [28]
01:37:00 - How cells know what type of cell to be
01:44:00 - Rolling the ball up the hill and ensuring it lands in the right groove.
01:46:30 - Antagonistic hallmarks
01:47:30 - Getting rid of scenescent cells - Senolytic Drugs
01:49:35 - Dietary restriction [29]
01:50:20 - Hormesis - what doesn’t kill you make you stronger [30]
01:51:51 - Intermittent fasting [31]
01:59:10 - Mitochondria and ROS [32]
02:03:00 - The challenge of Neurons
02:07:00 - The importance of change, earthseed
02:10:00 - Extending the female fertility window, ageing Oocytes
02:12:40 - structrutal mutations from mum and point mutations from dad
02:15:35 - Socio-economics of longer life
02:18:50 - MORE POWER!!! == MORE BETTER
02:23:18 - Mind Uploading & Cryonics [33-35]
02:24:10 - Technical challenges of mind uploading
02:25:50 - ‘Upload’ TV series [36,37]
02:27:20 - Bobiverse [38]
02:27:40 - Permutation City [39]
02:28:10 - Age of Em [40]
02:30:38 - Ethical Questions
02:31:40 - The Immortal dictator problem
02:32:20 - To what problem is mortality an acceptable solution?
02:34:40 - learn, work, retire, (repeat)?
02:39:05 - Transhumanism, i’ll take a better brain please
02:40:20 - Richard’s (Supervillan?) Origin Story
02:41:26 - I should not wish to outlive my friends
02:45:00 - I am a Strange loop, loss and conciousness [41]
02:46:50 - Harry Potter and the Methods of Rationality (chapter 39) [42]
02:52:50 - Surface Detail [43]
02:53:24 - Richard on The Bayesian Conspiracy [44]
02:53:00 - Outro

References

Differences between not ageing and being immortal:

• [1] https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/lifeexpectancies/bulletins/nationallifetablesunitedkingdom/2018to2020 - Current UK Life Expectancy (79.0M, 82.9F)
• [2] https://www.worldometers.info/demographics/life-expectancy/ - Global Life Expectancy (73.2)
• [3] https://en.wikipedia.org/wiki/Gompertz-Makeham_law_of_mortality - Gompertz–Makeham law of mortality
• [4] https://doi.org/10.1016/j.arr.2018.11.002 - Age-related diseases as vicious cycles
• [5] https://en.wikipedia.org/wiki/Negligible_senescence - Negligible senescence
• [6] https://www.goodreads.com/book/show/13530973-antifragile Antifragile: Things That Gain from Disorder (Incerto #4) by Nassim Nicholas Taleb
• [7] https://nationalhumanitiescenter.org/on-the-human/2010/08/temes-an-emerging-third-replicator/ memes & temes

Immortality and the Individual:

• [8] https://en.wikipedia.org/wiki/Turritopsis_dohrnii - ‘hydra’ Turritopsis dohrnii the ‘immortal’ jellyfish
• [9] https://en.wikipedia.org/wiki/Disposable_soma_theory_of_aging - Disposable soma theory of aging
• [10] https://en.wikipedia.org/wiki/Bristlecone_pine Bristlecone pine

Cellular Senescence:

• [11] https://www.hmpgloballearningnetwork.com/site/wounds/article/cellular-senescence-what-why-and-how - Cellular Senescence: What, Why, and How

The Hallmarks of ageing:

• [12] https://en.wikipedia.org/wiki/Antagonistic_pleiotropy_hypothesis - Antagonistic Pleiotropy (and the Selection shadow https://en.wikipedia.org/wiki/Selection_shadow)
• [13] Lopez-Otin et al. 2013 https://doi.org/10.1016/j.cell.2013.05.039 - The Hallmarks of Aging
• [14] https://richardjacton.github.io/thesis/introduction.html#the-biology-of-ageing - Summary of the hallmark from Richard’s PhD thesis

Telomeres:

• [15] The end replication problem: https://www.youtube.com/watch?v=8unMOUySGYY
• [16] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819049/ - How Telomeres Solve the End-Protection Problem
• [17] https://en.wikipedia.org/wiki/Hayflick_limit - Hayflick limit, maximum number of times a cell can divide

Ageing as signal transmission problem:

• [18] https://en.wikipedia.org/wiki/Claude_Shannon#Information_theory
• [19] Jenkinson et al. 2017 http://www.ncbi.nlm.nih.gov/pubmed/28346445 - Potential energy landscapes identify the information-theoretic nature of the epigenome. ~ - [20] ageless
• [21] https://en.wikipedia.org/wiki/Progeroid_syndromes - Progeriod (accelerated ageing)
• [22] Cagan et al. 2022 https://doi.org/10.1038/s41586-022-04618-z - Somatic mutation rates scale with lifespan across mammals
• [23] https://en.wikipedia.org/wiki/Error_catastrophe - Orgel’s Error Catastrophe

Epigenetics of Ageing and biological clocks:

• [24] https://www.nature.com/articles/d41586-022-00077-8 - Epigenetic Clocks
• [25] https://en.wikipedia.org/wiki/C._H._Waddington#Epigenetic_landscape - Waddington’s Epigenetic landscape
• [26] https://doi.org/10.1242/jcs.084822 - Cellular reprogramming and the Epigenetic landscape
• [27] https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell - Induced pluripotent stem cell, the Yamanaka factors
• [28] https://dx.doi.org/10.1186%2Fs13148-021-01158-7 - Review of Cellular reprogramming and epigenetic rejuvenation

Dietary restriction:

• [29] https://en.wikipedia.org/wiki/Calorie_restriction#Life_extension - Dietary restriction
• [30] https://en.wikipedia.org/wiki/Hormesis - Hormesis
• [31] https://en.wikipedia.org/wiki/Intermittent_fasting - Intermittent fasting
• [32] https://en.wikipedia.org/wiki/Free-radical_theory_of_aging - ROS / free radicals in ageing

Mind Uploading & Cryonics:

• [33] https://en.wikipedia.org/wiki/Cryonics - Cryonics

• [34] https://www.cryonicsunderground.com/ - Cryonics Underground Podcast

• [35] https://www.youtube.com/watch?v=2tdiKTSdE9Y - Tom Scott video about re-animating chilled hamsters with a microwave

• [36] https://en.wikipedia.org/wiki/Upload_(TV_series) Upload TV series

• [37] https://www.lesswrong.com/posts/SoqQ3ShW2xmdpjeZ7/why-rationalists-should-care-more-about-free-software Richard’s blog post, pertinent to not letting big corporations own your uploaded self.

• [38] The Age of Em: Work, Love and Life When Robots Rule the Earth by Robin Hanson https://www.goodreads.com/book/show/26831944-the-age-of-em

• [39] Permutation City (Subjective Cosmology) by Greg Egan https://www.goodreads.com/book/show/156784.Permutation_City

• [40] Bobiverse series starting with We Are Legion (We Are Bob) (Bobiverse #1) by Dennis E. Taylor https://www.goodreads.com/book/show/32109569-we-are-legion-we-are-bob

• [41] https://www.goodreads.com/book/show/123471.I_Am_a_Strange_Loop I Am a Strange Loop

• [42] Harry Potter and the Methods of Rationality (chapter 39) http://www.hpmor.com/chapter/39 audio: https://hpmorpodcast.com/?p=276, https://hpmorpodcast.com/?p=280

• [43] https://www.goodreads.com/book/show/7937744-surface-detail Surface Detail by Iain M. Banks

• [44] https://www.thebayesianconspiracy.com/2020/12/127-all-about-aging-with-richard-acton/ - The bayesian conspiracy Episode 127 – All About Aging with Richard Acton

Further Reading/listening:

Podcasts:

• David Sinclair: https://www.lifespanpodcast.com/
• lessons in lifespan health: https://lifespanhealth.usc.edu/lessons-in-lifespan-health/
• The Foresight institute: https://foresight.org/podcast/
• cryonics underground https://www.cryonicsunderground.com/
• Dr. Rhonda Patrick (PhD) of found my fitness has some great interview episode with leading aging researchers https://www.foundmyfitness.com/episodes She has a research background – complements the next recomendation
• The Peter Attia Drive (MD – medical background) good interviews with leading experts https://peterattiamd.com/podcast/

Books

Longevity

• David Sinclair https://lifespanbook.com/
• Age Later: Secrets of the Healthiest, Sharpest Centenarians by Nir Barzilai https://www.goodreads.com/book/show/51174975-age-later
• Ageless: The New Science of Getting Older Without Getting Old by Andrew Steele https://www.goodreads.com/book/show/52954648-ageless
• The Science and Technology of Growing Young: An Insider’s Guide to the Breakthroughs That Will Dramatically Extend Our Lifespan . . . and What You Can Do Right Now by Sergey Young https://www.goodreads.com/book/show/58267380-the-science-and-technology-of-growing-young
• The Longevity Diet: Discover the New Science Behind Stem Cell Activation and Regeneration to Slow Aging, Fight Disease, and Optimize Weight by Valter Longo https://www.goodreads.com/book/show/35697130-the-longevity-diet
• The Mystery of Human Aging: The Surprising Insights of a Science That’s Still Young by Bjeorn Schumacher https://www.goodreads.com/book/show/34956971-the-mystery-of-human-aging

Fundamentals / books that influence my thinking on this subject

• Scale: The Universal Laws of Growth, Innovation, Sustainability, and the Pace of Life in Organisms, Cities, Economies, and Companies by Geoffrey B. West https://www.goodreads.com/book/show/31670196-scale
• life’s ratchet Life’s Ratchet: How Molecular Machines Extract Order from Chaos by Peter M. Hoffmann https://www.goodreads.com/book/show/16691583-life-s-ratchet
• Antifragile: Things That Gain from Disorder (Incerto #4) by Nassim Nicholas Taleb https://www.goodreads.com/book/show/13530973-antifragile
• Every Life is on Fire: How Thermodynamics Explains the Origins of Living Things by Jeremy England https://www.goodreads.com/book/show/50358530-every-life-is-on-fire
• The Information: A History, a Theory, a Flood by James Gleick https://www.goodreads.com/book/show/8701960-the-information
• Freedom Evolves by Daniel C. Dennett https://www.goodreads.com/book/show/2071.Freedom_Evolves
• The Age of Em: Work, Love and Life When Robots Rule the Earth by Robin Hanson https://www.goodreads.com/book/show/26831944-the-age-of-em

Fiction

• Harry potter and the methods of rationality by Eliezer Yudkowsky http://www.hpmor.com/ (chapter 39 - ~24mins into the episode of the podcast version)
• Bobiverse series starting with We Are Legion (We Are Bob) (Bobiverse #1) by Dennis E. Taylor https://www.goodreads.com/book/show/32109569-we-are-legion-we-are-bob
• Permutation City (Subjective Cosmology) by Greg Egan https://www.goodreads.com/book/show/156784.Permutation_City
• Exhalation by Ted Chiang https://www.goodreads.com/book/show/41160292-exhalation (This is an anthology they are all good but I’m specifically referencing the titular story.)

---

Intro: L’Etoile danse (Pt. 1) by Meydan Outro: Long Way Home by Spinning Ratio