A study published in the journal Cell this past June, puts forth the groundbreaking concept that the activating component (TERT) of the enzyme telomerase is responsible for much more than telomere length as was once thought; it also targets DNA methylation throughout the genome and multiple hallmarks of aging. I believe this has the potential to change the way we look at the human aging process and our ability to modify it to our advantage. It is in a sense the follow-up to a 2011 Harvard study by the lead author, Ron DePinho in which he and his team effectively reversed aging in mice (admittedly mice that had been engineered to age quickly) by increasing the amount of the telomerase their cells produced.
Telomerase, you may recall, is the enzyme responsible for maintaining the lengths of our telomeres, the caps of repeated DNA sequences at the ends of our chromosomes. These caps protect our DNA during cell division, especially in oft-dividing cells like those in the immune system, gut, lungs, and skin. With each cell division, a small amount of genetic material is snipped off and lost, so that, over time, critically short telomeres cause DNA instability and halt further cell division, leading to cellular senescence, organ degeneration, cancer, and ultimately death.
DePinho’s mice visibly grew younger across the board, in a matter of months, in ways that seemed to go beyond an enhanced ability for certain cell types to keep dividing. At around the same time, I was involved in a small-scale clinical cohort study using a commercially-available, naturally-derived, telomerase-boosting supplement TA-65, that showed a remodeling toward a more youthful immune system. And for the past 17 years, I, and many of my patients, have been taking TA-65, with favorable results in two key immune system aging biomarkers.
A new era of longevity medicine seemed to beckon.
But the telomerase field cooled off. The consensus seemed to be that there was no practicable, safe way to upregulate telomerase (the TA-65 research, unfortunately, didn’t get the attention it deserved). Instead, a new dogma took root, that there were a bundle of interrelated physiological processes, including telomere exhaustion, the so-called Hallmarks of Aging, and if any one was more important than another, it was beyond our current abilities to discern.
And now the new Cell paper. DePinho’s team developed their own small-molecule telomerase-boosting drug and this time tested it on normally-aging mice. What they discovered was that telomerase’s age-slowing effects went beyond maintaining telomere length and cell division. Specifically, they found that a subcomponent of the enzyme, TERT (telomerase reverse transcriptase), responsible for adding the protective DNA segments to the chromosome ends, plays a much broader role. It serves as a transcription factor that affects a number of aging-related genes by working epigenetically. That is, it acts on the chemical messengers that turn the genes on or off, which determines whether the proteins they code for get produced or not. The more TERT in the cells, the greater the degree of methylation in the epigenome, the less active the genes responsible for making the proteins that collectively age us. This was observed both in the mouse model and in human cells cultured in vitro.
The biochemistry is complex but the results of this study should grab anyone: older mice whose telomerase had been boosted to youthful levels became, in effect, younger. To wit: less cellular senescence and less chronic inflammation generated by these aged “zombie cells”; protection against cognitive decline; enhanced production of new neurons in the brain’s hippocampus, central to memory; enhanced neuromuscular function, improving strength and coordination.
I was particularly excited by these results given my background researching, and taking, TA-65. DePinho’s conclusion, that TERT interacts more broadly with a host of relevant aging genes, may explain, not only the across-the-board rejuvenation that his mice experienced in his 2011 study, but also the improvement in the immune system profile of the patients I studied in my nearly contemporaneous research. It is certainly plausible that my patients and I have been enjoying some or all of the physiological benefits so meticulously documented in the Cell study. It’s impossible to say for sure. DePinho lab technology isn’t commercially available and, in any event, my patients and I avail ourselves of other therapies which would make it difficult to isolate a telomerase-specific health benefit.
What I can predict with more certainty is that researchers will take the new TAC (TERT activator compound) down the Big Pharma drug pathway, quite possibly within the next few years. Traditionally, they’ve taken a ‘go-slow’ approach because of the fear that upregulating telomerase could increase cancer risk – the unregulated growth of cancer cells is fueled by the enzyme. (As the DePinho group elucidated, one mechanism by which TERT does its good work is by downregulating a specific protein, p16, which acts as a guardrail against cancer cell proliferation.) But to date, no increased cancer risk has turned up, either in lab mice or in humans taking TA-65. Judging by the new paper, the scientific mainstream has grown bolder. Consider this line from the Cell article: “…the engagement of diverse aging mechanisms by TERT makes TAC treatment a viable strategy for aging per se and for specific associated aging-related diseases…” [The italics are mine.]
I can imagine a new conception of aging gaining acceptance – TERT, as far “upstream” in the aging process as we can now see, setting in motion many of the other Hallmark changes. And, as the Cell paper suggests in its diplomatic way, if we can safely manipulate TERT, we can successfully manipulate aging.
Shim HS, Iaconelli J, Shang X, et al. TERT activation targets DNA methylation and multiple aging hallmarks. Cell. Published online June 13, 2024:S0092-8674(24)00592-0. doi:10.1016/j.cell.2024.05.048
Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice. Nature. 2011;469(7328):102-106. doi:10.1038/nature09603
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278. doi:10.1016/j.cell.2022.11.001