Juvenescence Investing in the Age of Longevity ½ Empty? ½ Full? Keep Filling It Up!

12th November 2018 – Isle of Man

JUVENESCENCE INVESTING IN THE AGE OF LONGEVITY ½ EMPTY? ½ FULL? KEEP FILLING IT UP!

3 HCV Cure CRISPR

Cancer Artificial Intelligence Immunotherapy

4 1900 4747

1950 6868

Today 7979

2050 115

2100 ?

5 6 7 Disposable Soma Oxidative theory Of ageing

Evolutionary Theory of Ageing

Rate of living Second law Of Theory Thermodynamics

8 9

10 11 12 Healthy Aging

13 FOXO4

PPP

mTOR Cox7a1

Senescence

WICT

Autophagy -

Mitochondrial Myc

Klotho NF Uncoupling INDY Tet2

WILT

Sestrins

Transposons

NMN NAD+ WNT AMPK

NR p53 14 ility • Rapamycin is the only compound to extend life in all species studied to date

• Being tested in middle aged dogs in the Dog Aging Project

• TORC1 is an evolutionarily conserved pathway that regulates aging

• Advanced human clinical trials being run by resTORbio (NASDAQ:TORC) to improve immune function

• Oldest known attempt to extend lifespan • Circulatory systems of animals surgically joined • Used by Kim Il-Sung to the extend it changed his blood type from AB to B; he died age 82 • Modern version looks at specific “factors” in blood that provide the benefits and administering by transfusion • Ambrosia sells blood from younger people for USD 8,000 a pop!

17 • Cellular senescence – Phenomenon by which normal cells cease to divide – Dormant but metabolically active state – Promotes inflammation and accelerates ageing • Leonard Hayflick observed replicative senescence in 1960s – the Hayflick Limit • Caused by endogenous and exogenous DNA damage

Senolytic drugs can increase maximum lifespan by 35% in mice 18 WNT Pathway FOXO • Wingless-related integration site • Forkhead box family of transcription • Signalling pathway that regulates self- factors renewal and differentiation of adult stem – FOXO1 – insulin signalling cells – FOXO3 – tumour genesis – FOXO4 – Judith Campisi • Dysregulation of WNT in a specific tissue almost always leads to disease • Play a role in expression of genes involved in cell growth, proliferation, • Implicated in cancer and degenerative differentiation and longevity conditions • Believed to contribute significantly to the • Significant capital raised by Samumed (US immortality of the hydra $12b private market valuation) with lead indications in osteoarthritis and alopecia • Evolutionarily conserved in humans

19 Mice Treated from Middle Age Mice Treated in Old Age Maintenance of good health Even more impressive - rejuvenation

• Cardiac hypertrophy • Live ~35% longer • Kyphosis (curvature of • Dramatic extension of spine) health span • Loss of subcutaneous fat • Reduced locomotion • Cancer 20 Source: Baker & van Deursen et al. (2016) and Baar & de Keizer et al., (2017) • Increasingly important therapeutic strategy with vast application and potential: – Cartliage, heart failure, GVHD and many others

• Two key types of stem cells: – Embryonic • Ethical considerations • Pluripotent – Adult / somatic • Rare and few in number naturally • Induced pluripotent via Yamanaka transcription factors or small molecules • Lineage-restricted (multipotent) • Debate over therapeutic approach – Introduce exogenous stem cells – Stimulate activity of stem cells in situ 21

22 Metformin NAD+ Pre-cursors - Genomic Instability Parabiosis Rapalogs Brown Adipose Tissue Senolytics Klotho - Deregulated Nutrient Sensing Stem Cell Exhaustion NF-κB Advanced calorie restriction mimetics Telomere Attrition PPP Activation Mitochondrial dysfucntion iTR - induced tissue regeneration Amyloid targeting vaccines Thymus regeneration Lipofuscin removal Crosslink breakers Spermidine Loss of Proteostasis Mitochondrial gene therapy WILT WICT 23 1990 2000 2010 2020 2030 2040 2050 2060 Computing Internet Longevity

Tech IPOs Top 30 Longevity Companies

$45b $1.4b $40b $1.2b $35b $1.0b $30b $0.8b $25b Scientific breakthrough in cellular senescence $20b $0.6b $15b $0.4b $10b $5b $0.2b

$0b USD in year) (per Raised Funds Funds Raised in USD in year) (per Raised Funds $0.0b

$60b $76b 25 Source: Deloitte, National Institute of Aging, Mizuho Cancer Immunotherapy Biologics

$80b $400b

$60b $300b

$40b $200b

$20b $100b

Revenue peryear Revenue peryear Revenue $0b $0b 2013 2015 2022 1995 2015 2022

Source: GBI Research Source: Grand View Research 26 JUVENESCENCE.AI • Founders: – Jim Mellon – entrepreneur, author and investor – Greg Bailey – successful biotech entrepreneur Developing therapies – Declan Doogan – former head of R&D at Pfizer, Inc. that will allow people • Highly experienced investors, entrepreneurs to live longer and and drug developers with extensive network healthier lives. • Combining, artificial intelligence, classical drug development and aging research • Company has raised US $63m to date • Multiple additional pipeline opportunities • Contemplating IPO in 2019 28

JUVENESCENCE

29 Juvenescence is an operational therapeutics development company, not a fund

Identify compelling Provide guidance on opportunities – not clinical and regulatory science projects pathway

Return capital to Provide funding to shareholders through sale value inflection point or license of assets

No management or performance fees! • Novel technology to use lymph nodes as mini-bioreactors • When lymph nodes are seeded with purified hepatocytes (liver cells), the cells engraft and grow into small, functional ectopic livers • Livers only grow to size required by body • Bridge patients to transplant or completely supplanting the need for a transplant • Applications in other organs including the thymus and pancreas

Insilico Medicine, Inc. AgeX Therapeutics, Inc. Lygenesis, Inc. ∞ Johns Hopkins-based ∞ Leader in pluripotent stem ∞ Technology from University ∞ AI for aging research, drug cells and regenerative of Pittsburgh’s McGowan discovery and target medicine Institute for Regenerative identification ∞ Large proprietary set of Medicine ∞ Collaborations with GSK and industrial-scale human stem ∞ Use of lymph nodes as pilot program with J&J and cell lines bioreactors to grow Novartis ∞ induced Tissue Regeneration functioning ectopic organs ∞ JV - Juvenescence AI – immortal tissue ∞ Applications in the liver for regeneration end stage renal disease ∞ Strategic investment from WuXi Apptec (major Chinese ∞ VASC1 and BAT1 for diabetes ∞ Application in the thymus CRO) and ischemic disease for immuno-senescence

Netrapharma Napa Therapeutics, Inc. FoxBio, Inc. ∞ Novel mathematical ∞ Spinout from the Buck ∞ JV between Juvenescence technique to integrate the Institute for Research on and Antoxerene, Inc., a outputs of multiple different Aging subsidiary of Ichor machine learning algorithms ∞ Based on the discoveries Therapeutics, Inc. ∞ Extraction of valuable made at the lab of Dr Eric ∞ Developing small molecules information from minimal Verdin targeting a major survival pathway relied on by data ∞ Insilico Medicine will senescent cells ∞ Identification of non- identify small molecule responders, placebo modulators of an ∞ Multiple inhibitors of this response, and important undisclosed target target already identified correlates of drug response

33 Demographics

Corporate risks Health and long-term care risks

Macro and fiscal risks Pensions and social security risks

Labor market risks 34 • Pensions • Life insurance • Healthcare – BUT burden of care likely to decline • Leisure industry • Social care “I’ve crunched the numbers in your • Education retirement account. It’s time to figure out who will be wearing the mask and who will be driving the getaway car.”

36 Top 15 Pension Fund Liabilities £80,000m 207,965 103,599 153,345 122,320 122,320 115,094 £70,000m £60,000m £50,000m £40,000m £30,000m £20,000m £10,000m £0m

Pension Liabilities Market Cap 37 Top and Bottom 10 by Funded Status

60%

40%

20%

-20%

-40%

-60%

-80% Over / Under Funded Status Funded Under / Over -100%

38 Dividends Often Exceed Pension Deficit Shortfall £10,000m £8,000m £6,000m £4,000m £2,000m £0m -£2,000m -£4,000m -£6,000m

Pension Surplus / Deficit Dividends Paid 39 18.0% 16.0% 14.0%

12.0% 10.0% 8.0% % of GDP of % 6.0% 4.0% 2.0% 0.0% US UK Japan Germany France Italy Greece China

Black Monday – The The Stock Market Crash Stock Market Crash The British “Railway (1929) (1987) The Dot-com Bubble Manis” Bubble (1840s) (Late 1990s) Kuwait’s Souk al-Manakh Japan’s Bubble Economy The Dutch Tulip The Mississippi Bubble Stock Bubble & Crash (1980s) Mania (1634 – 1637) (1716 – 1720) The Florida Real Estate (1980s) Bubble (1920s) Longevity (2018 to ?) The Collapse of Barings Bank (1995)

The South Sea Bubble (1716 – 1720)

1600 2018 What percent of your wealth would you sacrifice to guarantee an extra 10 years of healthy life?

Net worth $50m+ 48%

Net worth $10m - $50m 38%

Net worth $2m - $10m 36%

Net worth $1m - $2m 32%

Source: The Century Club, UBS Private Bank 43 The market for anti-ageing treatments is currently worth USD 140 billion annually. Imagine how much the market will be worth when they actually work.