NOVEMBER 23-25, 2020

Click on links below to view recorded talks.


Biological systems are complex yet often guided by simple principles. These principles – rooted in physical laws – define the boundaries of the pitch on which evolution plays. These extend beyond species and represent the transferable mechanisms we seek in our fight against ageing and age-related disease. In contrast to most meetings that focus on the “what”, we aimed to foster a creative, open exploration of the physical limits and trade-offs behind why organisms have collectively converged on their solutions.

  This high-level discussion of the architecture of ageing was achieved by bringing together experts on a broad range of biological length scales. At the molecular level, we explored the necessary frailty of proteins to chemical and conformational ageing, and the inherent limits in detecting and clearing these altered forms – or proteoforms. Building on these principles, we discussed how metabolism interacts with the quality of proteomes and may be limited by it. We concluded by exploring the origins of information loss in ageing systems and its implications to an immune system that must distinguish self from non-self in an increasingly unrecognisable body.

DAY 1 Proteoforms & the limits of quality


Tom Kirkwood

Evolutionary trade-offs in ageing and disease.




Why deleterious proteoforms creep into proteomes

We start and end our lives with the same genes, yet our biological selves could not be more different, but why? Our proteomes are central to this puzzle, as the engines of accuracy and resilience. And yet, universally, proteomes become more chemically and conformationally altered with age. What are the mechanisms by which errors and entropy creep into our proteomes and what are the physical trade-offs necessitating their creation?

Ariel Lindner

Limits of accuracy, from mistranslation to post-translational modification.


Miro Radman

Protein damage and its conformational dependence.




Trade-offs in protein quality & triage

Once altered proteins are created, cells employ an array of tools for detecting, correcting or degrading them. However, detection is inherently inaccurate, creating a trade-off between efficiency and accuracy that manifests at multiple levels of protein quality control. How do cells decide whether to refold or degrade a distressed protein, and does the associated trade-off offer a lever for longevity?

Georgios Karras

Fantastic protein-folding mutants and where to find them.


Rahul Samant

Why we turnover our proteins and how it gets done.


DAY 2 Metabolism at stability’s edge


Metabolic limits of a vulnerable proteome

The double-edged sword of a respiration: much more ATP per glucose at the cost of free radicals. If the foldedness of proteomes determines the fraction of free radicals leading to fruitful signalling vs harmful damage, do cells regulate their metabolism to the health of their proteomes?

Stephen Treaster

Maintaining foldedness is a signature of longevity.


Anita Krisko

Metabolic choice in an unfolding world.


Nuno Raimundo

Mitochondria-lysosome crosstalk in ageing and disease.




Increasingly deviant in space & time

Ageing is not just a matter of average behaviour but of escalating variation at the level of transcription and translation, membrane potentials, cellular senescence, and beyond. Whether it be the stoichiometry of our proteins or our protons, what principles underlie this increasing variation in ageing, and do we die from declining averages or deviant black swans?

Michael Petrascheck

Transcriptional drift and protein imbalance.


Uri Alon

The dynamics of senescence.


Yifan Yang

Dynamic instability escalates to lethality.


DAY 3 Losing your sense of self


How a proteome catches a phenotypE

With ageing comes a gradual loss of protein quality, yet the dominant routes by which this leads to the phenotypes of ageing remain unresolved. Here, we explore different forms of fragility and discuss to what extent ageing and disease stem from a loss of beneficial functions versus a gain of deleterious ones.

Marc Vidal

Losing your edge in protein-protein interaction.


David Smith

Inhibition of proteasomes by small oligomers.


Fabrizio Chiti

Gain of function toxicity through loss of solubility.




Immune to healthy ageing

Heterogeneity of proteomes and metabolism increasingly blurs the line between self and non-self. How does the immune system find and fight its foes in an increasingly war-torn battlefield, and what is it really fighting? Does overactivation of our immune system ultimately lead to our demise?

Jamie Cunliffe

What gets the immune system up in arms?


Gerry Shadel




Roundtable TOPICS

Roundtables will allow participants to discuss their current beliefs on the topics presented and evidence that contradict them. It is meant to counterbalance the tendency of talks to overemphasise supporting evidence while underreporting opposing views.

Roundtable Day 1

What are the abundances of proteoforms and how do we detect them?

What are the limits and biases of detecting protein modifications with current technology? Are they mere reflections of normal physiology or biomarkers of dysfunction?


Why are proteins turned over so frequently?

Despite enormous metabolic cost, proteomes are constantly degraded and remade. What fitness trade-offs lead to the protein half-lives we observe across proteins, cell types, and organisms?

Roundtable Day 2

Free radical signalling: What defines too little and too much?

Many processes in biology have evolved to be as lean as possible while keeping the signal above the noise. Has free radical signalling evolved to these limits, and what opportunities does this provide?


What is the root cause of nuclear ageing?

With age, nuclei lose the ability to make transcripts in the right stoichiometry and in response to stress. Is it just about epigenetic marks, or is the ageing nucleus going through a phase change?

Roundtable Day 3

Is healthy ageing largely a loss of function while disease a deleterious gain of function?

What are the most universal properties of ageing organisms? What are the common triggers that distinguish healthy ageing from the development of disease?


Is our immune system overactive in old age?

How does our immune system distinguish self from non-self in an ageing body marked by increased heterogeneity at every level? Is the greatest pathogen ultimately ourselves?


If you are interested in joining the Methuselah Conference in 2021, please contact us at [email protected]