Highlights of Ending Age-Related Diseases 2020
LEAF organised the third of their, now annual, End Age-Related Disease conferences – held online this year, along with many other events, due to the coronavirus pandemic.
I listened in to as many talks as I could – discovering plenty of new ageing biology concepts, and also hearing the latest in ageing research from some of the leading scientists and entrepreneurs in the field.
If you missed it this year, I recommend attending in EARD 2021 if you can.
Here are some of the key points raised – sorted in speaker alphabetical order.
Alexander Fedintsev - Institute of Biology of the Komi Science Centre of the Ural Division of RAS
- Collagen glycation does not produce just vascular stiffness and wrinkle formation
- Stem cell aging can be arrested by exposure to young ECM
- Cellular senescence also linked to ECM, for example, exposing senescent fibroblasts to young ECM increases their proliferation
- Proposed that cellular senescence during ageing is the same response to fibrosis
Andrei Gudkov – Roswell Park Comprehensive Cancer Center
Has formed Genome Protection to commercialise antiaging therapies that target the retrobiome.
- Retroelements form 50% of DNA (“junk”).
- Not dead, but asleep.
- Aging can be considered a viral disease driven by virus-like patterns in our own DNA.
- Retrobiome is very active in tumours.
- Agonist of Toll-Like Receptor 5 works for acute radiation syndrome.
- Arranging clinical trial with Mayo Clinic to see if it has the same effect on ageing.
Aubrey de Grey - SENS Research Foundation
An ageing research conference wouldn’t be a conference without him…
- Suggested caution over Katcher's plasma treatment results until there are more results and details about the proprietary protein “elixir”.
- Welcomed Conboys’ similar results, though suggested diluting old factors won’t be the whole story.
- He was less concerned about the disappointing Unity trial failure as it may have been as much about an abnormally high placebo effect than poor performance of the senolytic. And generally, people seemed optimistic that there are plenty more senescence targets and drugs to come.
David Wood - London Futurists
Interviewed by Steve Hill from LEAF about humanity and longevity.
- Mobile technology saw slow change, followed by rapid change.
- Industrial revolution happened when tools were used to make more tools.
- Same is happening today allowing us to build better computers and software (including AI).
- Humans still in the loop, but will diminish
- Not just exponential growth – fast changes in biotechnology will happen only if a change in social acceptance
- One targeted breakthrough through might make people bolder
- Benefits of living longer include freedom to continue having experiences, longevity dividend 2.0 will be financially good for society, and better for the planet
- More people equals more ideas (using longer lasting knowledge & networks)
- We will have to give up some of our human nature - some people fear a slippery slope
- Need democratic control over new technologies. The problem with immortal dictators isn’t the immortal bit… it’s the dictator bit!
Gabriela Bunu - Institute of Biochemistry of the Romanian Academy
Presented a poster session on the SynergyAge database.
- The effect of combining genetic interventions is rarely additive.
- Synergy is when effect is greater than the sum of the components.
- Anti-synergy is when it is less.
- SynergyAge is a database of synergies (mainly in c.elegans).
- Most studied genes have most interactions (research bias).
- Some genes are not longevity genes themselves, but act as enhancers.
Hanadie Yousef – Juvena Therapeutics
Targeting age-related & degenerative diseases with pluripotent stem cells (PSCs).
- Identified youthful proteins in embryonic stem cells.
- Signalling proteins rejuvenated damaged tissue to youthful status.
- Using proprietary ML-enabled drug discovery platform.
- Identified a handful of proteins to use with high throughput robotic enabled screening.
- Optimising selected proteins to improve bioavailability.
- Has observed significant improvements in grip strength, endurance and fibre volume.
Irina Conboy – University of California, Berkeley
Probably one of the most anticipated presentations given the recent study of plasma dilution.
- Lifespan/healthspan is controlled by efficiency of repair
- Aging is malleable – can be reversed in many mammals
- Plasma dilution is not the only skeleton key (will need senolytics, etc).
- Starting company called IMYu and hopes to run Phase 2-3 clinical trials of rejuvenative plasmapheresis soon.
James Kirkland – Mayo Clinic
Provided a detailed update on the aging and senolytics.
- Risk of heart attack/stroke is 1000x greater at 80 compared to 30 - eclipses the 2-4x risk increase due to family history
- Over 40 influences push cells into senescence – though generally via p16/Rb or p53/p21 pathways
- Takes days to weeks for cell to become senescent
- Injected senescent cells into mice joints caused osteoarthritis
- 1 in 1000 cells is sufficient to drive frailty
- Senescence cells can spread locally and also to distant locations
- Senolytics should have a short half-life – hit and run on senescent cells
- 30 minutes exposure (in vitro) to dasatinib & quercetin killed senescent cells
- Improved remaining lifespan by 36% when mice treated at 24-27 months
- Don’t know what results will be in humans – should only be taken as part of a clinical trial
Jonathan Clark – Babraham Institute
Focussed on tendon collagen crosslinking – it may be way down the list of killers, but lessons learnt will no doubt about to other ECM crosslink disorders such as cardiac disease.
- Tendon ageing results in increased stiffness and increased stress at breaking point.
- Stress/strain plateau disappears after ~ 1 year in mice (~30 years old human).
- Stiffness not a good measure of ageing.
- Some enzymatic cross-links are reversible, but eventually mature into irreversible structures.
- Fixing imine bonding prevents reversal and gets rid of plastic phase.
- Decrease level of lysine glycation to improve initial elastic phase.
- To make tendon more youthful, decrease irreversible crosslinking – but only if able to increase reversible cross-links.
Joshua Mittledorf – Independent
Josh explains why he believes methylation clocks are the best measure of improvements from anti-aging interventions.
- Dysregulation is one kind of damage - can’t build a clock from random changes
- Two purposeful changes in methylation: (1) Response – repairing damage that accumulates with age, and (2) Driver – with the intention of creating more damage as part of an evolved aging program
- Both drivers and response can be used to make methylation clocks
- But only drivers are useful for evaluating anti-aging interventions
- Need to find patterns that correlate with detrimental changes
- Responses are counter-indications as they are improving cellular repair.
- 2013 DNAmAge is better predictor of mortality than chronological age
- 2018 PhenoAge (Levine) is better. Trained with other measures (e.g. blood biomarkers) but PhenoAge methylation clock performs better than PhenoAge itself.
- 2019 GrimAge (Ake Lu) is worse as it includes lifestyle + environmental factors, meaning it is probably rich in response sites. Though may be a good indicator of individual’s life left.
- Smoking may make you older by lung/artery damage – but not by reprogramming your methylation.
- Agnostic as to upstream cause of methylation changes.
Judith Campisi - Buck Institute
Discussed options for targeting senescent cells to alleviate ageing.
- Each cell type has its own SASP but core phenotype ~50%
- Can’t eliminate SASP as pathways are all critical for other important functions (e.g. DNA damage response).
- Pharmaceuticals can suppress it, but need to apply continuously as effect stops if medication stops.
- UNITY Biotechnology going for the alternative approach of eliminating senescence cells themselves.
- Many senolytics are failed anti-cancer drugs – but don’t have to kill every single target cell as required by chemotherapeutics – just lower burden by 70-80%.
- Most senolytics trials with mice improve median lifespan but not maximum lifespan.
Lewis Gruber – SIWA Therapeutics
- Lead Candidate is a cytotoxic antibody (318H) that binds to cell surface antigens
- Starting as a cancer therapeutic, later as a broad spectrum anti-viral
- Planning phase 1 trial in pancreatic cancer
Lorna Harries - University of Exeter
Presented evidence of age-related changes in alternative splicing (RNA processing) - one gene can make many different proteins and the ones chosen change with age.
- They have identified 2 molecules that restore the splicing to more youthful profile BUT they cancel in each out if both used... ageing is complicated!
- Lots of longevity genes are development genes
- Naked mole-rat splicing factors do not decline with time
- Turning splicing back on with small molecules (single treatment) resulted in half the number of senescent cells and restored telomere lengths.
- Commercialising senotherapeutic interventions with new company called SENISCA.
Marco Quarta – Rubedo Life Sciences
Design-engineered drugs only activate in selected cells.
- Proprietary chemistry improves specificity.
- Warhead molecules preferentially induce apoptosis in senescent cells.
- Reduced chemo-induced senescent cell burden by 80% in mice.
- Improved frailty, grip strength and cognition in 28-month old mice.
- RBO-1000 restores age-related loss of muscle stem cell functions.
- Planning cancer + pulmonary phase I trials in 2021-22.
Matthew O'Connor – Underdog Pharmaceuticals
Co-CEO reported on unpublished findings regarding atherosclerosis treatment.
- 7-Ketocholesterol (7KC) is useless and toxic.
- Lots in RBCs but not free floating in plasma.
- Need to be targeting 7KC with cyclodextrin derivatives – not all cholesterol.
- Uses CycloLab to synthesise new molecules.
- Created candidates with 10x potency (i.e. higher affinity) for 7KC target.
- Not trying to slow disease (like statins) - trying to stop and reverse it.
- Human clinical trials planned for 2023.
Peter Fedichev – Gero
Company’s founder explains how it is using AI to engineer rejuvenation therapeutics.
- Learnt biomarkers with unstructured AI training.
- Following individual humans – not just cohorts.
- We all have about 60 genes not being expressed.
- Using deep learning to see impact on biomarkers.
- Look for drugs that affect same pathways.
Polina Mamoshina – Deep Longevity (was Insilico Medicine)
Believes the time is now for AI due to advances in algorithms, reduced cost of GPU computing and big data – the millions of samples to train machine learning on. Noted that 14 AI-based tools were approved by FDA in 2017.
- Models trained on combined populations more accurate that those trained on specific population Key factors in biological age are fasting glucose, RDW, RBC, albumin and HDL Cholesterol.
- Age acceleration in tobacco smokers is only seen in under 50s, but your 60s smoking damage becomes less significant to other factors.
Reason – Repair Biotechnologies
Explained the company’s approach to reversing atherosclerosis.
- Even if reduce blood cholesterol to ridiculously low levels plaques will still build up.
- Cholesterol is used by cells for lots of other essential functions.
- HOFH patients have 10x level of cholesterol, but atherosclerosis is only condition they get.
- Will inject engineered macrophages to double/triple your natural population.
- Over-40s might undertake a treatment every 5-10 years to prevent atherosclerosis.
Steve Horvath - UCLA
Spoke about epigenetic clocks and how DNAm outperforms self-reported smoking pack years but doesn’t think that they will replace standard clinical measures (e.g. blood pressure, lipid levels, glucose) as they often have a cell type specific effect.
- Some epigenetic clocks can work for different mammals (e.g. humans/elephants, human/cat, human/rat) at the same time.
- Although naked mole rats don’t age he was still able to build a pan tissue clock, this could suggest that the long-lived mammal has developed a mechanism to deal with noise.
Vadim Gladyshev – Harvard Medical School
Believes ageing due to an increasing deleteriome.
- Deleteriome is broader than molecular damage.
- Most people have a few (~6) highly damaging mutations.
- Each mutation will reduce life expectancy by 6 months.
- Use a great analogy of ageing as a bolas – an ancient weapon made of weights on the ends of interconnected cords – as soon as on part hits the ground it all come crashing down.
Mentioned in this blog post:
Scientist, bioinformatician and machine learning engineer
Sr. Vice President, Basic Science at Roswell Park Cancer Institute.
Chief Science Officer at SENS Research Foundation. Author and advocate of ending ageing.
Chair at London Futurists
Research Assistant in Bioinformatics at Institute of Biochemistry of the Romanian Academy.
Co-founder and CEO of Juvena Therapeutics
Professor of Bioengineering at Berkeley University of California.
Researcher on different aging related diseases.
Head of Biological Chemistry at Babraham Institute.
Evolutionary biologist and author of the Playing the Game for a Longer Life blog
Professor of biogerontology and Biochemist.
CEO, CSO and Co-Founder of SIWA Therapeutics
Professor of Molecular Genetics at the University of Exeter.
Co-Founder CEO at Rubedo Life Sciences.
Co-Chief Executive Officer and Co-founder of Underdog Pharmaceuticals.
Founder of Gero and physicist in drug discovery land.
Chief Scientist and Chief Operating Officer at Deep Longevity and Head of Biomarker Development at Insilico Medicine.
CEO of Repair Technologies and founder of Fight Aging
Professor of Human Genetics & Biostatistics at UCLA
Professor of Medicine at Harvard Medical School.
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