aging: the first obstacle to transhumanists 2...worms autophagy oxidative phosphorylation, mtor...
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October 20, 2018
TransVision
Madrid, Spain
Aging: The First Obstacle to
Transhumanists
João Pedro de Magalhães
Integrative Genomics of Ageing Group
Institute of Ageing and Chronic Disease
University of Liverpool, UK
2
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TransVision 2001
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“The knowledge that every ambition is doomed to
frustration at the hands of a skeleton have never prevented
the majority of human beings from behaving as though
death were no more than an unfounded rumor.”
Aldous Huxley
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50% of people die
within 14 years (75%
in 25 year period)
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What will kill you
~50% will die of heart disease and cancer
Almost 75% will die of heart and vascular disease,
cancer and neurodegenerative diseases
Ageing is a sexually transmitted terminal disease
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0%
20%
40%
60%
80%
100%
0 500 1000 1500 2000 2500 3000 3500
% a
live
Age (yrs)
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Species with negligible senescence
Galapagos photo by Matthew Field; other photos in Public Domain
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age-1 identified in 1988
Ageing can be manipulated
by genes and interventions
“...it’s possible that we
could change a human
gene and double our life
span.” – Cynthia Kenyon
Ageing process is plastic
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Entries in GenAge Mice Flies Worms Yeast Total
Number of genes 136 193 877 909 2,152
Greatest lifespan
increase46% 150% 10-fold 6-fold -
Tacutu et al. Nucleic Acids Res, 2018
With Fraifeld lab (Israel)
Genes modulating longevity
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Longevity pathways from GenAge
Fernandes et al. Hum Mol Genet, 2016
Species Pro-longevity Anti-longevity
Mice p53-signaling pathway
and cell cycle
growth hormone and insulin
signaling, IGF-1 receptor
Flies hypoxia response via HIF
activation
PI3 kinase pathway,
oxidative phosphorylation
and IGF pathway
Worms autophagy oxidative phosphorylation,
mTOR signaling pathway
Yeast ribosome
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It is possible to manipulate ageing
Ageing is not merely the sum of age-
related diseases
Manipulations of genes, inc. by diet
and drugs, could dramatically
improve human health
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McCay et al. 1935. J Nutrit 10:63-75.
Caloric restriction
Reducing calories extends
healthy lifespan and delays
age-related diseases
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Okinawans undergo mild CR and have
better health
CR can help identify drug target genes
(e.g., rapamycin which targets TOR)
“You can live to be a hundred if you give up all the things that make you want to live to be a hundred.” ― Woody Allen
de Magalhaes et al. Pharmacol Rev, 2012
CR health paradigm
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http://genomics.senescence.info/drugs/
Barardo et al. Aging Cell, 2017
1316 entries from 27 model organisms
418 drugs/compounds
325 publications
Drugs modulating longevity
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Big data approaches
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Repurposing compounds for life-extension
de Magalhaes et al., Pharmacol Rev, 2012;
Calvert et al., Aging Cell, 2016
Overlap between longevity
signatures and drugs
4/5 drugs tested in worms
extended lifespan (inc. allantoin)
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Burgeoning anti-aging biotech sector
de Magalhaes et al., Trends in Biotech, 2017
Consult/advisor:
Five Alarm Bio, Xobaderm,
Ingenet, P3M Clinic, Apollo
Thera, Genescient,
Androcyte, 4D Pharma,
Aviva
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Playing devil’s advocate
Few % companies becomes profitable
Only 1/5000 drug candidates obtains
approval
Long validation times in aging
de Magalhaes et al., Trends in Biotech, 2017
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Drug longevity effects in animals
Barardo et al. Aging Cell, 2017
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From model organisms to humans
de Magalhaes et al., Trends in Biotech, 2017
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Human ageing remains a mystery
Poor biological understanding of human ageing
Poor understanding of the genetics of human longevity
de Magalhaes Cell Cycle, 2014; Trends in Biotech, 2017
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• Ageing remains a mystery of biology
– Why do we age?
• Genes (>2000) and drugs (>400) can extend longevity
in animals
– Will they extend human longevity? And by how much?
• Big data to prioritize drugs and targets
– How can we predict clinical outcomes?
• Growth in anti-ageing biotech
– Which intervention will work?
Summary & questions
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http://pcwww.liv.ac.uk/~aging/
Lab members:
Daniel Thornton,
Dominic Bennett,
Jacob Edogbanya,
Daniel Palmer, Kasit
Chatsirisupachai,
Saara Marttila,
Daniela Martinez,
Gulam Altab,
Priyanka Raina,
Roberto Avelar
Funding sources: