Using somatic evolution as a human aging timer

As a core component of combined aging clocks, Cell Tree Rings could mitigate current uncertainty in assessment of geroprotective trials.

Aging is a dynamic process; however, any measurement taken of aging is a snapshot of the state of play at a particular time. But how can we know what went on before that snapshot and at what speed? How can we compare the two and make predictions for the future?

Enter Cell Tree Rings, an approach that considers the shape of cell lineage trees by looking at a combination of branch lengths and branching patterns and uses that shape to determine aging status.

Longevity.Technology: All living things age and trees are no exception; as they get older, trees form distinctive rings, outward from the centre, with a new circle of wood laid down each year. These rings can tell us not only the age of the tree, but what the climate was like in each year or the level of pollution and can also reflect water stress, bending from wind or snow, defoliation from insects, forest fire or disease.

Somatic cells are body cells, as opposed to germ or reproductive cells. Somatic mutations – changes in the DNA sequence of somatic cells – are a part of aging, occur throughout the lifespan either spontaneously as a result of errors in DNA repair mechanisms or a direct response to stress. Environmental stressors can increase the mutation risk as can intracellular processes that generate free radicals as they cause cellular damage and mutations within DNA. Once a mutation has occurred, the newly-altered DNA undergoes normal cellular replication and becomes incorporated into all subsequent cell lines from that original cell.

The concept that somatically arising mutations play a crucial part in aging is one of the oldest aging theories, and the Hallmarks of Aging framework puts genome instability, partly manifested as somatic mutations, as the first, foundational hallmark. However, somatic mutations are not well explored in geroscience, with only a few experts labs and companies having experience in the field. This is perhaps because the evidence about somatic mosaicism being everywhere in the body of healthy humans, and that clonal hematopoiesis of indeterminate potential (CHIP) can be associated with increased risk of not just cancer, but cardiovascular, autoimmune and neurodegenerative diseases, to name but a few, has only really been accumulated in the last decade (see this review for latest updates on this topic).

Now a group of researchers has posited that somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. By inferring cell lineage trees from these mutations, the researchers have been able to reflect the somatic evolutionary process and they hypothesise, the aging status of the body [1].

Previously this sort of clock has been impractical due to the significant technological challenge of detecting somatic variants in single cells.

The researchers included AgeCurve’s Attila Csordas, Professor Damien G Hicks, Physics/Statistics Professor at the Swinburne University in Melbourne, Australia and Botond Sipos, a phylogeneticist, computational biologist and sequencing expert.

They detected somatic mutations using single-cell RNA sequencing (scRNAseq) from hundreds of cells and constructed a cell lineage tree whose shape correlates with chronological age. The team used de novo single-nucleotide variants (SNVs) that had been detected in human peripheral blood mononuclear cells using a modified protocol.

A single cell tree from each of the 18 participants in the study. To estimate uncertainty in the tree shape metrics, a total of 25 pseudo-replicate trees were inferred for each participant. Each tree is constructed from a random sample of 700 cells out of the ∼1400 from that individual.

Using penalised multiple regression the researchers selected from over 30 possible metrics characterising the shape of the phylogenetic tree, resulting in a Pearson correlation of 0.8 between predicted and chronological age and a median absolute error less than 6 years. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and has potential as a new modality of aging timer [1].

In addition to providing a single number for biological age, Cell Tree Rings unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. This new platform complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.

Not measuring existing somatic mutation burden before an intervention, which is the current default practice, can potentially offset biological age assessment by decades, and not assessing the potential changes in that burden due to and after the intervention can miss important additional mechanisms, effects and opportunities.

While the paper describing Cell Tree Rings has not yet been peer reviewed, AgeCurve Ltd has filed a patent called Cell Tree Rings: method and cell lineage tree based aging timer for calculating biological age of a biological sample. The team are also raising a bigger seed round in order to turn their invention into a proper innovation.

Longevity.Technology went out on a limb and reached out to Attila Csordas, founder and CEO of AgeCurve, and the driving force behind Cell Tree Rings.

He told us that in biology, is always a good bet to use the tools and insight of quantitative phylogenetics – the real brain power behind evolutionary thinking.

“Cell Tree Rings is the first industry-developed, scalable and application focused tool that is ready to unleash the power of evolutionary cell lineage trees using somatic mutations in healthy people from hundreds/thousands and potentially many more individual cells,” says Csordas. “It achieves this goal by a methodological disruption, calling somatic mutations from a modified version of the most available and affordable scRNAseq protocol by 10x Genomics.

“This is order of magnitude cheaper than the current, mostly academic single cell DNA sequencing of whole genomes to build reliable trees and it provides transcriptomics data directly from the same cells that mutations are coming from. The other key component is comprehensive cell tree statistics where we have used advanced math solutions from signal processing/physics to factor in every bifurcation on the tree.”

Csordas explains that in contrast to other companies, AgeCurve now has a disruptive technology, with patent pending, that can deliver “without bluffing” using the potential of somatic evolution.

“We are in a position now to raise a bigger round,” he says. “Currently we are working with the Healthy Longevity Clinic to turn the initial results into clinically useful and actionable insights by analysing the actual underlying somatic mutations in the top cancer driver genes.

“But the applications of Cell Tree Rings go much further than this and it can be directly used in pharma and biotech from CHIP studies to cancer drug efficacy testing and regenerative medicine amongst others.”

Csordas also noting that the expertise and assistance of Healthy Longevity Clinic’s Dr František Zámola and Longevitytech.Fund‘s Petr Šrámek were instrumental in getting Cell Tree Rings up and running.

The researchers have called for further co-operation, urging those running geroprotective trials, academic researchers, and people involved in clinical and industry settings to get in touch if they would like to use Cell Tree Rings.