Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 [email protected] http://www.sens.org/ Dr Aubrey de Grey Chief Science Officer 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 Dr Aubrey de Grey Chief Science Officer 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? Dr Aubrey de Grey Chief Science Officer What is… - Regenerative medicine? - Aging? Dr Aubrey de Grey Chief Science Officer What is regen med? Any intervention that seeks to restore the structure of a tissue/organ to its state before it suffered damage Dr Aubrey de Grey Chief Science Officer What is aging? Metabolism ongoingly causes “damage”. Damage eventually causes pathology. Dr Aubrey de Grey Chief Science Officer Options for intervention Gerontology Metabolism Geriatrics Damage Pathology Dr Aubrey de Grey Chief Science Officer Problem: this is metabolism Dr Aubrey de Grey Chief Science Officer 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. Dr Aubrey de Grey Chief Science Officer This is the damage Seven Deadly Things Cell loss, cell atrophy Division-obsessed cells (cancer) Death-resistant cells Mitochondrial mutations Intracellular junk Extracellular junk Extracellular crosslinks No new type of damage confirmed since 1982! Dr Aubrey de Grey Chief Science Officer Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Damage rising with age Cell loss, cell atrophy Division-obsessed cells (i.e. cancer) Death-resistant cells It or its effects reversible by Cell therapy, mainly Telomerase/ALT gene deletion plus periodic stem cell reseeding Suicide genes, immune stimulation Mitochondrial mutations Allotopic expression of 13 proteins Intracellular junk Extracellular junk Extracellular crosslinks Transgenic microbial hydrolases Phagocytosis by immune stimulation AGE-breaking molecules/enzymes Dr Aubrey de Grey Chief Science Officer Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Some parts are in clinical trials Damage rising with age Cell loss, cell atrophy Division-obsessed cells (i.e. cancer) Death-resistant cells It or its effects reversible by Cell therapy, mainly Telomerase/ALT gene deletion plus periodic stem cell reseeding Suicide genes, immune stimulation Mitochondrial mutations Allotopic expression of 13 proteins Intracellular junk Extracellular junk Extracellular crosslinks Transgenic microbial hydrolases Phagocytosis by immune stimulation AGE-breaking molecules/enzymes Dr Aubrey de Grey Chief Science Officer 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 Dr Aubrey de Grey Chief Science Officer Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Other parts are making headlines Damage rising with age Cell loss, cell atrophy Division-obsessed cells (i.e. cancer) Death-resistant cells It or its effects reversible by Cell therapy, mainly Telomerase/ALT gene deletion plus periodic stem cell reseeding Suicide genes, immune stimulation Mitochondrial mutations Allotopic expression of 13 proteins Intracellular junk Extracellular junk Extracellular crosslinks Transgenic microbial hydrolases Phagocytosis by immune stimulation AGE-breaking molecules/enzymes Dr Aubrey de Grey Chief Science Officer Dr Aubrey de Grey Chief Science Officer Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Others are early but exciting Damage rising with age Cell loss, cell atrophy Division-obsessed cells (i.e. cancer) Death-resistant cells It or its effects reversible by Cell therapy, mainly Telomerase/ALT gene deletion plus periodic stem cell reseeding Suicide genes, immune stimulation Mitochondrial mutations Allotopic expression of 13 proteins Intracellular junk Extracellular junk Extracellular crosslinks Transgenic microbial hydrolases Phagocytosis by immune stimulation AGE-breaking molecules/enzymes Dr Aubrey de Grey Chief Science Officer Intracellular junk in the artery Endothelial Cells Lipidengorged Lysosome Foam Cell Dr Aubrey de Grey Chief Science Officer 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… Dr Aubrey de Grey Chief Science Officer 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 Dr Aubrey de Grey Chief Science Officer Environmental decontamination in vivo Dr Aubrey de Grey Chief Science Officer 7-ketocholesterol degradation a promising start 7KC over time in enrichment 7KC over time in cultures enrichment cultures units] 500 450 400 350 300 250 200 150 100 50 0 0 2 4 6 day 8 days 10 Biodegradation 2008; 19(6):807-813 Dr Aubrey de Grey Chief Science Officer Stable isotope labelling and LC/MS reveal 7-ketocholesterol metabolites in the culture supernatant 7-ketocholesterol M = 400, M13C = 401 Dione metabolite ? M = 398, M13C = 399 Hydroxylated dione ? M = 414, M13C = 415 OH HO O O O O O Culture growing on 7-ketocholesterol Culture growing on 13C-labeled 7-ketocholesterol Dr Aubrey de Grey Chief Science Officer COX/LAMP1 co-localizes with AO Acridine Orange EGFP Merge Dr Aubrey de Grey Chief Science Officer pEGFP-COXL1 transfected cells are protected from 7KC-induced toxicity Mathieu et al., Biotechnol. Bioeng. 2012; 109(9):2409-2415 Dr Aubrey de Grey Chief Science Officer neural retina RPE Age-related accumulation of fluorescent compounds in retinal pigment epithelium Dr Aubrey de Grey Chief Science Officer Fundus autofluorescence (= RPE lipofuscin) increases with age Exc.: 550 nm Individually corrected for lens absorption Delori et al., IOVS 42:1855. 2001 Dr Aubrey de Grey Chief Science Officer MOD FA A major constitutent of RPE lipofuscin is the fluorescent pigment A2E Eldred and Lasky, 1993 Sakai et al., 1996 Parish et al., 1998 Dr Aubrey de Grey Chief Science Officer A2E pyridinium bisretinoid Sakai, Decatur, Nakanishi and Eldred, 1996 Dr Aubrey de Grey Chief Science Officer Amphiphilic compound 2 hydrophobic side-arms cationic polar head Cl - Cl - A2E iso-A2E Dr Aubrey de Grey Chief Science Officer Dr Aubrey de Grey Chief Science Officer Dr Aubrey de Grey Chief Science Officer Steps to biomedical application 1) Isolate competent strains; select by starvation. 2) Identify the enzymes (mutagenesis, chemistry, genomics). 3) Make lysosome-targeted transgenes; assay cell toxicity. 4) Assay competence in vitro (more mutagenesis/selection). 5) Construct transgenic mice; assay toxicity in vivo. 6) Assay competence in disease mouse models. 7) Test in humans as for lysosomal storage diseases. Dr Aubrey de Grey Chief Science Officer 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) Dr Aubrey de Grey Chief Science Officer 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 [email protected] Dr Aubrey de Grey Chief Science Officer 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 [email protected] Dr Aubrey de Grey Chief Science Officer