Aching joints and wrinkled skin are an unwelcome part of aging, but in the future, you might be able to avoid arthritis medications and cosmetic procedures by getting a shot of TERT activator compound (TAC). A young-at-heart team identified this small molecule, which increases transcription of a telomerase subunit called TERT. The upshot is that a little TAC leads to more youthful human and mouse cells, as well as adult mice with more spring in their step.
Mutations in telomerase components can lead to premature aging but forcing expression of a telomerase subunit called TERT (telomerase reverse transcriptase) can reverse some markers of aging. To find small molecules that could activate TERT, Ronald DePinho’s lab (The University of Texas MD Anderson Cancer Center) and colleagues (The Scripps Research Institute) screened 653,000 compounds with mouse cells transgenic for the human TERT gene with a luciferase reporter. Here’s what they found:
- Out of about 100 hits, one stood out, and they called it TAC (TERT activator compound)
- TAC boosts TERT mRNA in primary human fibroblasts in a dose-dependent manner
- TAC treatment increases H3K27ac and reduces H3K9me3 around the TERT promoter
- Injection of TAC elevates human TERT expression in transgenic mouse tissues
- In proliferating and non-proliferating primary cells, TAC causes the endogenous mouse Tert gene to be expressed
- In prematurely aging Werner syndrome (WS) fibroblasts, TAC induces TERT expression, and the cells grow longer telomeres
With a youthful curiosity, the team wondered how TAC works. Using phosphor-kinase assays, they saw that TAC increases phosphorylation of ERK (extracellular signal-regulated kinase) and S6 kinase, which is downstream of ERK in primary human MRC-5 cells. Of the genes they examined, FOS is upregulated the most in normal human fibroblasts and induced pluripotent stem cell-derived neurons. FOS is part of the AP-1 transcription factor complex and is important for TAC-induced TERT upregulation.
Reactivating TERT rejuvenates old mice that have telomere damage, so the team wanted to know whether injecting TAC in naturally aged mice could reverse aging. Here’s what they found after treating with TAC:
- TERT protein levels increase and aging markers, such as cell cycle arrest, go down
- Repression of p16Ink4a, a protein that drives senescence, via DNA methylation at CpGs
- Improved cognitive and neuro-muscular function, as well as new neuron growth and reduced neuroinflammation
- No obvious negative side effects
“These preclinical results are encouraging, as TAC is easily absorbed by all tissues, including the central nervous system,” shares DePinho. He adds that the work reveals how TAC and TERT work, thereby uncovering new druggable targets that could be explored to help treat aging-related diseases, such as Alzheimer’s disease and cancer.
At”TAC”k the details at Cell, July 2024.