Aubrey de Grey questioned whether a single gene can show if a cell retains its type during partial reprogramming
Aubrey de Grey questioned whether a single gene can show if a cell retains its type during partial reprogramming
On August 17, Michael West cited a time course of two genes during brief activation of the Yamanaka factors, proteins that alter gene activity. Aubrey de Grey replied that an early marker of the transition toward an unspecialized state rises only slightly before TERT, a gene associated with telomerase. Their exchange raised a practical question: which changes show that a cell has altered its age-related measures while still retaining its type.
Prolonged activity of the Yamanaka factors (OSKM) drives a cell toward pluripotency, a state from which different cell types can develop. With brief OSKM activation, researchers are looking for a regime in which age-related measures have already shifted while the cell remains specialized.
In an August 17 post, West writes that brief OSKM expression may “reverse developmental processes, as occurs in cloning.” For clinical use, he calls this approach “induced tissue regeneration” and cites a time course from a 2018 study.
The graph compares ZFP42 and TERT. ZFP42 is an early marker of movement toward pluripotency. TERT encodes the catalytic component of telomerase, the enzyme that maintains chromosome ends. In his reply, de Grey points to how closely the two curves track each other:
“The rise in ZFP42 precedes the rise in TERT only slightly.”
A brief OSKM pulse needs to be assessed using a time course of several cellular programs: age-related measures, markers of the original cell type, early and late markers of pluripotency, and TERT. The sequence of these changes shows which programs the cell has already passed through.
In the 2018 study, researchers tracked human fibroblasts, connective tissue cells, for 49 days after OSKM activation. Epigenetic age, which they estimated from marks on DNA, began to decline between the third and seventh days and reached zero on their epigenetic clocks by day twenty. ZFP42 and other early pluripotency genes rose sharply during the first ten days and reached a stable level by day twenty. The activity of genes associated with the original specialization of fibroblasts remained high until day fifteen. After that, the cells lost this profile.
Epigenetic clocks trained on normal aging may fall outside their range of validity when a cell changes its identity. The state of a cell after a brief pulse is therefore described using several measures.