Ronald DePinho MD {his CV
By 1.46 in the video
Here is a tidy transcript, summary, and critique of the YouTube presentation:
Video: “Can We Treat Aging? | Telomeres and TAC” by Dr. Ronald DePinho
Tidy Transcript (Condensed and Cleaned)
Speaker: Dr. Ronald DePinho
Topic: Aging as a treatable biological process
“Aging is something we will all face — it’s universal and underpins major diseases such as cancer, diabetes, heart disease, and Alzheimer’s. As we age, the incidence of these diseases increases dramatically. But aging is now coming into molecular focus.
For a long time, we defined aging vaguely — a gradual decline. But real progress requires understanding the mechanisms behind aging. Just as we learned that mutations drive cancer, we now understand the hallmarks of aging — genomic instability, inflammation (“inflammaging”), mitochondrial dysfunction, accumulation of senescent (zombie) cells, and telomere attrition.
Telomeres protect chromosomes. Over time, they shorten and fray, leading to genomic instability and premature cellular aging. An enzyme called telomerase reverse transcriptase (TERT) maintains telomeres. But we’ve discovered it also has a secondary role — regulating gene expression linked to a youthful state.
As we age, levels of TERT drop sharply. This may trigger many aging hallmarks. So the question arose: Can we restore TERT levels pharmacologically?
We screened one million compounds and identified a molecule we call TAC (TERT Activator Compound). TAC restores TERT to youthful levels, penetrates all tissues including the brain, and only needs to be dosed three times per week.
We treated aged mice (equivalent to 70-year-old humans) with TAC and observed dramatic results:
- Regeneration of neurons in the hippocampus (linked to memory)
- Reduction of senescent cells and inflammation
- Improved muscle strength, balance, and immunity
- No significant side effects
We then tested TAC in a mouse model of Alzheimer’s disease. Compared to untreated mice, TAC-treated animals had:
- Fewer amyloid plaques
- Reduced neuroinflammation
This suggests that we can intervene in aging itself, which is the shared origin of many age-related diseases. Instead of reactive care, we could shift toward regenerative medicine, extending healthspan rather than just lifespan.
Imagine being in your 90s, active and mentally sharp. Aging is not destiny — it’s biology. And biology, through science, can be changed.”
Summary
Main Claims:
- Aging is the common underlying cause of most chronic diseases.
- Telomere dysfunction is central to aging.
- A molecule called TAC, developed by the speaker’s team, restores TERT levels and reverses multiple aging hallmarks in mice.
- Treated mice show improved cognition, physical ability, immune function, and resistance to Alzheimer’s pathology.
- Aging could be treated proactively — not just its symptoms, but its root causes.
Key Results:
- In normal aged mice: Improved neurogenesis, reduced inflammation, enhanced muscle function, no toxicity.
- In Alzheimer’s model mice: Reduced amyloid plaques, less neuroinflammation.
Proposed Vision:
- Shift from sick care to regenerative medicine.
- Extend healthy years (healthspan), compress morbidity.
Critique
Strengths:
- Clear framework: Anchored in the “hallmarks of aging” concept.
- Biological plausibility: Telomere biology is well-established in aging literature.
- Innovation: The dual role of telomerase (telomere repair + transcriptional regulation) is compelling.
- Promising preclinical data: Improvements in cognition and muscle function in mice treated late in life is rare in aging research.
Limitations & Questions:
- Mouse model limitations:
- Mice do not perfectly model human aging.
- Alzheimer’s mouse models often fail to translate to human outcomes.
- TERT and cancer risk:
- TERT activation is also linked to oncogenesis. This risk wasn’t addressed in detail, though short half-life and intermittent dosing may mitigate it.
- Lack of human data:
- The talk is entirely preclinical. No mention of human trials or safety profiling beyond mice.
- Mechanistic vagueness of TAC:
- The chemical structure, mechanism of TAC beyond “TERT activation,” and downstream pathways are not shown.
- Is it activating transcription directly? Epigenetically remodeling chromatin?
- Marketing vs. science balance:
- The tone leans toward advocacy of a miracle molecule. Caution and scientific caveats are underemphasized.
Overall Impression
This is an inspiring and scientifically grounded talk on aging, focused on telomerase and a new therapeutic (TAC). While the preclinical results are striking, the leap to human rejuvenation is still speculative without clinical trials. Nonetheless, it’s a valuable contribution to the emerging paradigm of aging as a modifiable process.
If you’d like, I can help locate peer-reviewed publications by this speaker or group on TAC or TERT mechanisms.
2 Likes
If we knew what TAC was and its mechanism then it would be more interesting. I think Telomerase is important because it acts on improving mitochondria as well as telomeres. I don’t think replicative senescence is that big a thing.
I imagine that Dr DePinho’s team are working on a proprietary version of one of the known TERT Activator Compounds below?
- TA-65: A natural compound derived from Astragalus membranaceus, often marketed as a telomerase activator.
- AGS-499: A synthetic telomerase activator studied for its neuroprotective effects.
- GRN510: A telomerase activator that showed promise in idiopathic pulmonary fibrosis (IPF) models.
- Cycloastragenol: The active ingredient in TA-65, thought to upregulate telomerase in somatic cells.
1 Like
Can’t find the video but somewhere Aubrey de Grey mentioned that just increasing telomerase can cause cancer to grow and he thought doing a therapy that destroys cancer cells and then do a telomerase therapy would allow you to receive the benefits without risking cancer.
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In a study of 17 people from five families, Johns Hopkins Medicine researchers say they found that ultra-lengthy DNA endcaps called telomeres fail to provide the longevity presumed for such people. Instead, people with long telomeres tend to develop a range of benign and cancerous tumors, as well as the age-related blood condition clonal hematopoiesis
“Our findings challenge the idea that long telomeres protect against aging,” says Mary Armanios, M.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center, and professor of genetic medicine, molecular biology and genetics, and pathology at the Johns Hopkins University School of Medicine. “Rather than long telomeres protecting against aging, long telomeres allowed cells with mutations that arise with aging to be more durable.”
Armanios directs the telomere center at the school of medicine. The center includes a laboratory-based service that provides telomere length testing for clinical diagnostics, a multidisciplinary clinic that serves people with telomere syndromes, and a group that conducts fundamental telomere research.
Long telomeres in cells grown in the lab have been shown to predict cellular longevity, but this study suggests that, in people, the longer-lived cells can cause problems, Armanios says. “Cells with very long telomeres accumulate mutations and appear to promote tumors and other types of growths that would otherwise be put in check by normal telomere shortening processes,” she says.
Such tumors were found in 12 of the 17 people in the two-year Johns Hopkins study. Ranging in age from 7 to 83, the study participants experienced goiters (enlarged thyroid glands), various types of melanoma, lymphomas, other cancer types and uterine fibroids. Some of the participants had more than one of these conditions. Four patients who died during the study had lymphoma, colon cancer, leukemia and a brain tumor.
Published study below.
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What I think happens with telomeres is that if the mitochondria are not efficient enough then they don’t get extended hence a cell will hit replicative senescence. That is good because bad mitochondria can cause cancer.
I don’t think replicative senescence causes much of a problem in aging in itself beyond it preventing cancer.
See also: Possible side-effects of sulfonamide drugs
The mechanism was studied (see below) in the paper which first reported TAC. The MEK/ERK pathway is generally considered a pro-aging pathway, with drugs like the MEK inhibitor trametinib considered possible longevity drugs. Separately, the AP-1 family of transcription factors has been reported to push chromatin states along pro-aging trajectories (see: The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening). I think it’s still a very interesting drug, but these are definitely concerns.
TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription
To gain insight into the downstream signaling cascades and TERT promoter elements linked to TAC-induced TERT expression, we first analyzed the phosphorylation profiles of kinases and their substrates, using phospho-kinase arrays. We found that phosphorylation of extracellular signal-regulated kinase (ERK) and its downstream effector S6 kinase was consistently increased by TAC treatment in primary human MRC-5 cells (Figures 2A and 2B). Accordingly, inhibition of ERK with the MEK inhibitor trametinib abolished TAC-induced ERK phosphorylation and TERT upregulation in MRC-5 cells (Figures 2C and S2A).
Next, we investigated transcriptomic changes across different somatic cell types to elucidate potential transcription factors and their binding elements linking ERK activation to TERT transcriptional control. Through transcriptome profiling of human normal fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons, we observed that acute treatment with TAC (0.5 μM for 1 h) resulted in the significant induction of only a limited number of common genes in both human cell types (Figure 2D). Strikingly, only two genes, FOS and SOGA3, exhibited significant upregulation in both cell types following treatment (≥ 2-fold cutoff; p < 0.05), with FOS—encoding a major constituent of the activator protein 1 (AP-1) transcriptional complex—identified as the gene most significantly regulated by TAC in both cells (Figures 2E–2G). In addition, TAC treatment did not elicit any significant change in the global translation rate (Figure S2B), providing evidence that TAC treatment specifically induces TERT expression and its downstream transcriptional effects without affecting general mRNA translation.
The FOS gene encodes a critical component of AP-1 transcription factor complex, which binds to specific cis-acting elements on gene promoters stimulating the expression of these target genes. We identified two AP-1 binding sites residing within the 4-kb upstream regulatory region of the human TERT gene, with one of these binding motifs well conserved between human and mouse (Figures 2H and 2I). To explore whether these loci are required for TERT promoter activation, we constructed a human TERT promoter-luciferase reporter containing 4-kb upstream sequences from the transcription start site of the TERT gene. Following transient transfection of MRC-5 cells with these luciferase reporter constructs, we stimulated the cells with TAC. Consistent with our observation of endogenous TERT levels, TAC induced TERT reporter activity in human fibroblasts (Figure 2I). Of note, single and double deletions, including the AP-1 binding motif common in the promoters of both mouse and human, significantly abolished TAC-induced TERT promoter activity (Figure 2J), highlighting that the conserved AP-1 cis-element has a more prominent function in mediating TERTtranscription compared with the other. We next assessed whether the AP-1 complex is specifically recruited to the TERTpromoter in response to TAC treatment in their endogenous chromatin context. Chromatin immunoprecipitation followed by real-time quantitative PCR (ChIP-qPCR) analysis showed that TAC treatment led to recruitment of endogenous FOS, a subunit of AP-1 complex, to two AP-1 binding motifs in the endogenous TERT promoter (Figure 2J). A selective AP-1 inhibitor T-5224 that specifically blocks FOS/AP-1 binding to DNA without affecting their expression³³ impaired TAC-induced expression of TERT (Figures 2K and S2C). Together, these data indicate that TAC specifically activates the transcriptional activation of TERT via the MEK/ERK/AP-1 pathway.
Interestingly chatGPT says
But the image does not have three fluorines
Looking at this it does not seem right. I think I found it before, but probably that needs to be found in the forum
- TA-65: A natural compound derived from Astragalus membranaceus, often marketed as a telomerase activator.
- GRN510: A telomerase activator that showed promise in idiopathic pulmonary fibrosis (IPF) models.
- Cycloastragenol: The active ingredient in TA-65, thought to upregulate telomerase in somatic cells.
These 3 are all the same thing.
CAG naming
In the process of searching documents, we found that CAG (CAS number: 78574-94-4) is noted by diverse names in different documents. CAG is named (2aR,3R,4S,5aS,5bS,7S,7aR,9S,11aR,12aS)-3-((2R,5S)-5- (2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-2a,5a,8,8-tetramethylhexadecahydrocyclopenta[a]cyclopropa[e]phenanthrene-4,7,9-triol, other synonyms include CAG, CA, astramembrangenin, cyclogalegigenin, GRN510, and TA-65. TA-65 was named by the T.A Science Corporation as a nutrition and health care product. A document reported that GRN510 is a novel and proprietary chemical entity derived from GRN665/TAT2. However, GRN510 is considered equivalent to CAG in PubChem (an open chemistry database); therefore, we considered GRN510 as equivalent to CAG in this article. For simplicity, we termed cycloastragenol as CAG in this report.
The image I posted is the correct structure of TERT-activating compound/TAC, it’s taken directly from the paper which discovered it.
European Journal of Medicinal Chemistry Reports
Volume 5, August 2022
Titled;
“A comprehensive review of cycloastragenol: Biological activity, mechanism of action and structural modifications”
https://www.sciencedirect.com/science/article/pii/S2772417422000322