"The Science of Aging" by Martin Borch Jensen
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Slides from the inaugural Impact.tech seminar about the science of aging, healthspan and longevity. The presentation addresses questions such as: What is aging? Is aging treatable? What are the major biological processes that make up aging? What are the major breakthroughs in anti-aging science? How you can get involved in anti-aging as an entrepreneur or investor? Impact.tech Launch Seminars are meant to give entrepreneurs and investors a launch into a topic where they can apply their skills to make a major positive impact for humanity and the world.
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"The Science of Aging" by Martin Borch Jensen
- 1. Community of people excited about combining profit with purpose www.impact.tech #impacttech
- 2. The Science of Aging Where we are and where we could go Martin Borch Jensen Y Combinator Research July 13, 2017
- 4. According to NIH grant review panels: Experience: Who am I? Nanobiotechnology M.Sc Ph.D. DNA repair Accelerated aging Mitochondria Protein aggregation
- 5. Aging as a problem Mechanisms of aging Where do we stand?
- 6. c c c c Aging is a growing challenge
- 7. Aging is the ultimate risk factor 10 200 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 Age / years Diseaseincidence/% Cancer Cardiovascular Dementia Diabetes $88B in USA $318B in USA $259B in USA $176B in USA
- 8. S m o kin g D iet S ed entary lifestyle O ccu p atio n al exp o su re F a m ily h isto ry V iru se s Perin atal A lco h o l S o cio eco n o m ic statu s Po llu tio n U V radiatio n D ru gs & M ed ical p ro ce d u res S alt & fo o d ad d itives Risk factors for cancer Aging is the ultimate risk factor More accurate risk factors for cancer Aging
- 9. NIH research funding Cancer Heart/lung/blood $5.1B $3B Diabetes & Kidney $2B Neuro/ Stroke $1.6B Aging $1.2B Alzheimer’s $13BAge-related diseases ≈5% Aging research is not being funded
- 10. US healthcare spending (≈$4T) NIH research spending Total disease spending Aging research is not being funded x3→
- 11. "It may be defined as a process of unfavorable progressive change, usually correlated with the passage of time, becoming apparent after maturity and terminating invariably in death of the individual.“ A. I. Lansing The 1951 version: The 2017 version: Defining “Aging” “Comprehensive and progressive decline of physiological function over time.”
- 12. Solanas & Benitah, Nat. Rev. Mol. Cell Biol. 2013 Not visible signs of aging…. …but underlying processes Causes rather than symptoms
- 13. Not extending sick state… …but slowing deterioration, stretching healthy lifespan SickHealthy Healthspan and lifespan
- 14. Measuring aging But molecular “clocks” are appearing Horvath epigenetic clock Right now, gait may be our best biomarker
- 15. Early investments haven’t paid off Why isn’t aging research funded?
- 16. Why isn’t aging research funded?
- 17. Is anything different now? Why isn’t aging research funded?
- 18. Life extension in daf-2 mutant worms Kenyon et al., Science, 1993 Single genes can alter aging rates
- 19. Mouse 2-3 years Bat 20 years Naked mole rat 28 years Biodiversity of aging
- 20. Turritopsis dohrnii T. dohrnii life cycle Aging is reversible
- 21. T. dohrnii don’t show increased mortality over time Turritopsis dohrnii Martinez et al., Exp. Geront. 1998 Aging is reversible
- 22. [Intermission]
- 23. Aging as a problem Mechanisms of aging Where do we stand?
- 24. Biology is universal (with porting challenges) Yeast Mammals
- 25. Biology is universal (with porting challenges)
- 26. There are no ‘Laws of Biology’
- 27. The central dogma of biology: Information flows from DNA, through RNA, to proteins. Each step contains all necessary information. DNA RNA Protein There are no ‘Laws of Biology’
- 28. Apoptosis pathway Everything is multifactorial and dynamic
- 29. Schoenfeld & Iodannis, Am. J. Clin. Nutr. 2012 Cancer risk with high consumption of… Results are highly context-dependent
- 30. Organismal Cellular DNA Proteins Metabolism Tissues Stem cells Intercellular signaling Things that break with age
- 31. McLeod et al., Biogerontology, 2016 Male, 24 years Male, 66 years Male, 66 years Physically active Sarcopenia/Muscle loss Tissues lose functional cells with age
- 32. Tissues lose functional cells with age Osteoporosis/Bone loss
- 33. Imbalanced cellular populations with age Breakdown > Buildup = Bone loss
- 34. Adapted from Akunuru & Geiger, Trends Mol. Med. 2015 Aging Imbalanced cellular populations with age Blood cell imbalance causes immune dysfunction
- 36. DNA RNA DNA damage causes loss of information A U G C A C A G U G U C A U C Ile Gln Cys His
- 37. ~23,000 genes 13 genes Nuclear Mitochondrial DNA exists in two parts of the cell
- 38. Adapted from Westermann, Nat. Rev. Mol. Cel. Biol. 2010 Mitochondrial DNA mutations can spread Mitochondrial “life cycle”
- 39. Trifunovic et al., Nature 2004 Mitochondrial mutations accelerate aging Mitochondrial ‘mutator mouse’ ‘Mutator mouse’ has short lifespan
- 40. Lifespan extension by telomere lengthening in old mice De Jesus et al., EMBO Mol. Med 2012O’Sullivan & Karlseder, Nat. Rev. Mol. Cell Biol. 2010 Telomeric DNA may limit lifespan Telomeres buffer ends of chromosomes
- 41. Chromatin packing is lost with age Oberdoerffer & Sinclair, Nat. Rev. Mol. Cell Biol. 2007 Hutchinson-Gilford Progeria Syndrome
- 43. Proteins must fold correctly Translation Chaperone-mediated folding Functional protein
- 44. Lopez-Otin et al., Cell 2013 Misfolded proteins are damaging Protein cleanup mechanisms
- 45. Simonsen et al., Autophagy 2008 Misfolded proteins are damaging Stimulating protein cleanup extends lifespan
- 46. New Scientist Other protein accumulation also matters
- 47. Protein activity affects everything
- 49. Life extension in daf-2 mutant worms Kenyon et al., Science, 1993 Many ‘aging genes’ regulate metabolism
- 50. Colman et al., Science 2009 Calorie restriction slows aging 30% CR in rhesus monkeys, age 28 years Incidence of age-related disease in CR monkeys
- 51. Harrison et al., Nature 2009 Bitto, Ito et al., eLife 2016 Regulating growth signaling affects aging Rapamycin treatment in old, outbred mice Short-term rapamycin treatment in old mice
- 52. Riera & Dillin, Nat. Cell Biol. 2015 Mitochondria are a metabolic signaling hub Mitochondrial coordination of metabolism
- 53. Abundance causes damage Abundant food & growth signaling Scarce food & protective signaling CR Interventions
- 55. Stem cells exist in most tissues
- 56. Stem cells self-renew upon division Ito & Suda, Nat. Rev. Mol. Cell Biol. 2014 Stem cell division
- 57. Stem cells self-renew upon division Ito & Suda, Nat. Rev. Mol. Cell Biol. 2014
- 58. Stem cell pools deplete with age Ito & Suda, Nat. Rev. Mol. Cell Biol. 2014 Aging
- 59. 100 µm Adapted from Fry et al., Nat. Med. 2014 StemcellsdepletedControl Before 7d after injury Stem cell depletion impairs regeneration
- 60. Adapted from Akunuru & Geiger, Trends Mol. Med. 2015 Aging Stem cell depletion impairs function
- 61. De Los Angeles & Daley, Nature 2013 ‘Stemness’ is a cellular program
- 62. Restoring stem cells can rejuvenate
- 64. Young blood contains rejuvenating factors Young serum Adapted from Science 2015 Heterochronic parabiosis
- 65. Villeda et al., Nature Med. 2014 Young blood rejuvenates the brain Increase in dendritic spines Improved learning capacity
- 66. Inflammation
- 67. In fla m m a to ry c y to k in e s Bloodconcentration(a.u.) T N F - IL -6 s T N F R -II 0 2 4 6 A g e 1 8 -3 0 A g e 5 5 -6 5 A g e 8 0 A g e 1 0 0 + * * * * p < 0 .0 5 v s . 1 8 -3 0 c o h o rt * Adapted from Bruunsgaard et al., J. Geront. 1999 Aging increases chronic inflammation Increase in circulating inflammatory factors with age
- 68. Chronic inflammation is bad for you
- 69. Munoz-Espin & Serrano, Nat. Rev. Mol. Cell Biol. 2014 Senescent cells are a source of inflammation Normal and aged senescence-associated inflammation
- 70. Baker et al., Nature 2016 Clearing senescent cells improves health Appearance and lifespan of senescence-cleared mice
- 71. Organismal Cellular DNA Proteins Metabolism Tissues Stem cells Intercellular signaling Things that break with age
- 72. Moving away from single-cause theories Lopez-Otin et al., Cell 2013Neal Fedarko A 1956 view of aging
- 73. Fundamental questions remain unresolved Is aging caused by random damage or a biological program? Is there a single/a few root causes of age-related decline? Is the decline of multiple systems connected or independent?
- 74. [Intermission]
- 75. Aging as a problem Mechanisms of aging Where do we stand?
- 80. Limitations of academia • Reductionist approach, looking at 1-2 phenomena at a time
- 81. Limitations of academia • Reductionist approach, looking at 1-2 phenomena at a time • We talk about translational research, but can’t do it
- 83. Limitations of academia • Reductionist approach, looking at 1-2 phenomena at a time • We talk about translational research, but can’t do it • We generate large(ish) data sets, but rarely use extensively Single candidate gene/pathway
- 86. Tools to accelerate therapies Biomarkers Delivery/ Gene therapy & more… Lab automation
- 88. FDA approves drugs for manifested damage 10 200 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 Age / years Diseaseincidence/% Cancer Cardiovascular Dementia Diabetes YES NO
- 89. Aging may become recognized by FDA
- 91. Bitto, Ito et al., eLife 2016 Off-patent candidates aren’t pursued
- 92. Who is developing aging therapeutics?
- 93. Calico Recruiting prominent professors Focus on basic research No clear strategy announced Who is developing aging therapeutics?
- 94. Sequencing everything Disease detection Not an aging company Who is developing aging therapeutics?
- 95. & others Senescent cell clearance: Who is developing aging therapeutics?
- 96. Startups in: Regeneration Supplements Parabiosis & more Who is developing aging therapeutics?
- 97. Some focused funds: David Gobel Laura Deming James Peyer Who is developing aging therapeutics?
- 98. Knowledge Development Treatment Age-related diseases Academia FDA Prevent aging Reverse aging ? Investors Pharma Compounds FoundersSenolytics Tools Aging Foundations Rapamycin Metformin
- 99. Summary • Aging costs society trillions of dollars per year (and sucks). • Human aging is a biologically solvable problem. • We understand many of the factors, but not the whole system. • We need better tools to understand and address root causes of aging. • Most findings aren’t translated to therapies (especially the good stuff). • There is no cavalry.
- 100. Summary Don’t Instead Start a Ph.D. in biology Befriend a Ph.D. in biology Look for a solution to all age-related damage Get anything approved for treating human aging Wait for the scientists to figure everything out Enable faster research
- 101. What to do next • Investors: Please choose 2 existing companies that you think would be good investments for monetary returns and for making an impact on aging. • Entrepreneurs: Please devise 2 companies that you think could do well and have an impact on fighting aging. Martin and Michael will then review and come back with any particular insights or challenges that apply to your choices.
- 102. Questions and discussion Curiosity is good, but making an impact is better. Let’s concentrate on what you need to know to make decisions about starting, joining or investing in companies that are fighting aging.