Thread by @sciencescanner

Diseases of ageing are quite distinct from conventional diseases with a genetic basis - revealsed by the incidence profile with age #MethuselahHealth

Diseases of ageing occur because the machine wears out rather than because one of the components was faulty. Ageing is a property of the system not its parts…

EVERYONE ages, no matter what your genome!

#MethuselahHealth

The paradigm for pharma has become the “genetically-validated target” - which has proved excellent at fixing diseases caused by defective parts (mostly the “rare diseases”). But it totally fails in the prevalent age-related diseases, where the system falls apart

But repeated failure beyond treating the symptoms of age-related disease has let many pharma’s to retreat entirely from the battle and focus their attention on the low-hanging fruits of genetic disease

#MethuselahHealth has the inisght to re-open the bigger fight!

The key initial inisght came from our Scientific Founder, Prof Miro Radman - his expts reminded us that the so-called central paradigm of molecular biology (DNA->RNA->Protein) is incomplete: proteins are needed to make & repair DNA, make RNA, make more proteins, do EVERYTHING

Here’s the key experiment in the amazing radiation-resistant bug D radiodurans, that can survive 5Gy ionising radiation! This shatters the DNA (as it does in susceptible bugs like E Coli)… but because D Radiodurans PROTEINS survive they can repair the DNA

When I saw the results from this experiment in 2012, it cured me of my “DNA-centricity” (forbes.com/sites/davidgra…). I realised that ageing is about proteome stability, not genomic stability

#MethuselahHealth

So proteins make DNA make RNA makes proteins… a self-replicating system. Unfortunately, information theory tells us that such systems are fundamentally unstable - any error is compounded over time until the system fails

#MethuselahHealth

Fortunately, you can overcome errors by correcting them. And silicon valley wasnt the first to come up with the idea of back-ups… DNA is double-stranded for precisely this reason. And thats why you accumulate remarkable little mutational load as you age

But the proteome has no back-up. If you make an error when making a ribosome, the resulting ribosome will be more error-prone in making proteins. As a result, your proteome will begin to drift from the perfect, genome-encoded version you were born with

#MethuselahHealth

I like the analogy of a fairground mirror - as you get older the proteome increasingly deviates from the genome. Old people are, quite literally, made of poorer-quality versions of the same proteins as their younger selves (and if you doubt that, just look in the mirror!)

Collecting evidence for this drift, however, requires recognition of “quantum-resolution” proteomics - the concept that each individual instantiation of a protein (each molecule) is potentially different from all the others

To delve into this quantum-resolution, you need to modify the conventional proteomics workflow to focus on the ability to accurately quantify each PEPTIDE rather than to estimate the abundance of each PROTEIN. Thats not as easy as it sounds!

To do this we have made numerous changes to create our own proprietary proteomics platform called Proteoformer™ - its at least 10x more powerful an quantifying peptides in complex mixtures than anything described in the public domain

Using Proteoformer™ we can quantify two types of quantum diversity: errors (making bad copies of the protein in the first place) and damage (either deliberate, such as phosphorylation, glycosylation or cleavage) or unintended (oxidation, deaminidation, proteolysis)

Using this platform we can generate data to see, for the first time, the proteome drift that is actually occuring during human ageing - but there will be a break in the “live tweeting” because unfortunately I cant share that data just yet… apologies

Why does this proteome drift matter? If the genome is mostly in tact, enough of the protein molecules are still functional…

But as the proteome diversifies it starts to narrow the distinction between self (what you tolerised against - “young you”) and foreign

Thats a simplification of course - the immune system changes its threshold for detecting non-self over your life to give you maximum protection from infection for the minimum self-destruction. But eventually the trade-off becomes impossible - then atrophy, then death!

This is nicely illustrated by #COVID19 of all things… in old people, the lower innate immune reactivity allows the virus a bigger headstart before adaptive immunity kicks in. But worse than that, when the virus does activate complement it hits the “old proteome” much harder!

So enough theory, what about some experimental evidence? We used type 2 diabetes (and its complications) as a model of accelerate ageing - comparing serum samples from people with diabetes with closely-matched individuals without, using Proteoformer™

Among several hundred proteins in serum that we have good resolution detection of the quantum zoos, 11 showed significant difference due to the presence of diabetes that survived correction for false-discovery rates

And six of those eleven are directly or indirectly associated with excess activation of complement: C3 and Factor B are components of the AP C3 convertase, and properdin stabilises that complex

We see the serpin anti-chymotrypsin (forming covalent complex with Factor D, the upstream activator of Alternative pathway of Complement), plus haptoglobin and haptoglobin-related protein complexes, indicative of elevated complement mediated RBC lysis

Our observation of altered complement activation in diabetes, secondary to accelerated proteome drift, are only correlations… BUT diabetic complications phenocopy rarer genetic mutations that CAUSE over-activation of complement

#MethuselahHealth