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

TransVision 2001

“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

50% of people die

within 14 years (75%

in 25 year period)

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

0%

20%

40%

60%

80%

100%

0 500 1000 1500 2000 2500 3000 3500

% a

live

Age (yrs)

Species with negligible senescence

Galapagos photo by Matthew Field; other photos in Public Domain

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

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

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

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

McCay et al. 1935. J Nutrit 10:63-75.

Caloric restriction

Reducing calories extends

healthy lifespan and delays

age-related diseases

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

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

Big data approaches

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)

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

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

Drug longevity effects in animals

Barardo et al. Aging Cell, 2017

From model organisms to humans

de Magalhaes et al., Trends in Biotech, 2017

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

• 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

http://pcwww.liv.ac.uk/~aging/

aging@liverpool.ac.uk

Lab members:

Daniel Thornton,

Dominic Bennett,

Jacob Edogbanya,

Daniel Palmer, Kasit

Chatsirisupachai,

Saara Marttila,

Daniela Martinez,

Gulam Altab,

Priyanka Raina,

Roberto Avelar

Funding sources: