Regenerative medicine for aging: are we reaching the knee of the exponential curve? Aubrey D.N.J. de Grey, Ph.D. Chief S

1. Regenerative medicine for aging: are we reaching the knee of the exponential curve? Aubrey D.N.J. de Grey, Ph.D. Chief Science Officer, SENS Foundation aubrey@sens.org http://www.sens.org/

2. SENS Foundation SENS Foundation is a US-registered charity that works to develop, promote and enable widespread access to regenerative medicine solutions to the disabilities and diseases of… AGING

3. But surely <insert favourite knee-jerk reaction>? • Treating aging is just preventative geriatrics • Old people are people too, deserve health • Is medicine good only so long as it doesn’t work very well? • Was the Industrial Revolution a bad thing? • How much did Jenner/Pasteur understand?

4. What is… • Regenerative medicine? • Aging?

5. What is regen med? Any intervention that seeks to restore the structure of a tissue/organ to its state before it suffered damage

6. What is aging? Metabolism ongoingly causes “damage”. Damage eventually causes pathology.

7. Options for intervention Gerontology Geriatrics Metabolism Damage Pathology

8. Problem: this is metabolism

9. Options for intervention Gerontology Maintenance Geriatrics Metabolism Damage Pathology Claim: unlike the others, the maintenance approach may achieve a big extension of human healthy lifespan quite soon.

10. This is the damage Cell loss, cell atrophy Division-obsessed cells (cancer) Death-resistant cells Mitochondrial mutations Intracellular junk Extracellular junk Extracellular crosslinks Seven Deadly Things No new type of damage confirmed since 1982!

11. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation

12. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Some parts are in clinical trials

13. About those amyloid trials… • Clinical endpoints not achieved • Amyloid is removed • Tau is not • No one knows what causes what in AD • Combination therapies = wings + engine

14. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Other parts are making headlines

16. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Others are early but exciting

17. Intracellular junk in the artery Endothelial Cells Lipid-engorged Lysosome Foam Cell

18. Bioremediation: the concept Microbes, like all life, need an ecological niche. Some get it by brawn (growing very fast)… …some by brain (living off material that others can't). Any abundant, energy-rich organic material that is hard to degrade thus provides selective pressure to evolve the machinery to degrade it. That selective pressure works. Even TNT, PCBs…

19. Xenocatabolism: the concept Graveyards are abundant in human remains, accumulate bones (which are not energy-rich), do not accumulate oxysterols, tau etc., so, should harbour microbes that degrade them… …whose catabolic enzymes could be therapeutic

20. Environmental decontamination in vivo

21. 7-ketocholesterol degradation a promising start 7KC over time in enrichment cultures days Biodegradation 2008; 19(6):807-813

22. Stable isotope labelling and LC/MS reveal 7-ketocholesterol metabolites in the culture supernatant 7-ketocholesterol M = 400, M13C = 401 Hydroxylated dione ? M = 414, M13C = 415 Dione metabolite ? M = 398, M13C = 399 Culture growing on 7-ketocholesterol Culture growing on 13C-labeled 7-ketocholesterol

23. COX/LAMP1 co-localizes with AO Acridine Orange EGFP Merge

24. pEGFP-COXL1 transfected cells are protected from 7KC-induced toxicity Mathieu et al., Biotechnol. Bioeng. 2012; 109(9):2409-2415

25. Age-related accumulation of fluorescent compounds in retinal pigment epithelium neural retina RPE

26. Fundus autofluorescence (= RPE lipofuscin) increases with age Exc.: 550 nm Individually corrected for lens absorption Delori et al., IOVS 42:1855. 2001 MOD FA

27. A major constitutent of RPE lipofuscin is the fluorescent pigment A2E RPE lipofuscin A2E Eldred and Lasky, 1993 Sakai et al., 1996 Parish et al., 1998

28. A2E pyridinium bisretinoid Sakai, Decatur, Nakanishi and Eldred, 1996

29. Cl - Amphiphilic compound 2 hydrophobic side-arms cationic polar head Cl - iso-A2E A2E

32. Steps to biomedical application Isolate competent strains; select by starvation. Identify the enzymes (mutagenesis, chemistry, genomics). Make lysosome-targeted transgenes; assay cell toxicity. Assay competence in vitro (more mutagenesis/selection). Construct transgenic mice; assay toxicity in vivo. Assay competence in disease mouse models. Test in humans as for lysosomal storage diseases.

33. A word about “MetaSENS” • SENSF does research to implement SENS • But is that enough? Three reasons why not: • Is SENS complete? (Vijg lab): “prot pleio” • Is SENS needed? (Reis lab): “weather” • <cue interminable digression re primate CR> • What will SENS cause? (Hughes group)

34. Learn more Read the (semi-technical) book. Available at Amazon and all good book stores. Paperback is cheaper, and has an extra chapter! Visit us on the web at http://www.sens.org/ Drop us a line at foundation@sens.org

35. SENS Foundation SENS Foundation works to develop, promote and ensure widespread access to regenerative medicine solutions to the disabilities and diseases of aging. www.sens.org aubrey@sens.org