Slow Aging? No, REVERSE Aging!

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Who knew? And All you have to do is eat tacos three times a week!

How could we reverse aging? | Ronald DePinho | TEDxFordhamUniversity

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Do people want a transcript, summary critique from O3?

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https://www.nature.com/articles/s12276-024-01297-w

Metformin seems to stabilize telomere length at least in some tissues.

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Worthless mechanistic study which doesn’t translate into an actual life-extending effect in mice nor in humans.

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Mice had to have tacos 3 times a week. I don’t know how often people would need to, but I’d say less often. Like once a year?

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As requested:

1. Tidied transcript

(Speaker – Dr Ronald A. DePinho, TEDxFordhamUniversity, published June 2025)

0 : 00 – 0 : 28
Applause – Thank you. I’m here to talk about something everyone acquires and no one escapes: ageing. For millennia it was a mystery, but it’s finally coming into focus and the findings will, I believe, change the human experience.

0 : 28 – 1 : 25
Ageing is the common soil that underlies cancer, diabetes, heart disease and Alzheimer’s. Globally, 1.2 billion people are over 60. After 60 the incidence of these diseases doubles roughly every five years, giving lifetime risks of ~40 % for cancer and dementia by 85.

1 : 25 – 2 : 11
Until recently we defined ageing only descriptively: the gradual accumulation of damage. But to treat it we need its molecular and cellular drivers. As mutations drive cancer, specific processes drive ageing.

2 : 11 – 3 : 10
Nine “hallmarks” outline those processes: genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence (“zombie cells”), stem-cell exhaustion and chronic inflammation (“inflammageing”).

3 : 10 – 4 : 21
My lab has focussed on telomeres, the protective chromosome caps. When they fray and shorten, chromosomes become unstable, triggering premature cellular ageing. The enzyme telomerase (specifically its catalytic sub-unit TERT) maintains telomeres. Besides lengthening telomeres, TERT moonlights with transcription factors to keep youthful gene‐expression programmes alive.

4 : 21 – 5 : 06
We showed TERT protein levels fall sharply at the very onset of ageing, initiating the other hallmarks. What if we could restore youthful TERT?

5 : 06 – 6 : 03
We screened ~1 million molecules and discovered a family of two related compounds – we call the scaffold TAC (TERT-Activator Compound). TAC penetrates every tissue, crosses the blood–brain barrier, and a short half-life means it need be given only three times per week.

6 : 03 – 7 : 00
Trial 1: naturally aged mice. We began dosing at 22 months (roughly a human in their 70 s) and treated for six months. At 28 months (human 90 s) we examined the hallmarks.

7 : 00 – 8 : 12
Results were striking. In the hippocampus—key to memory—new neurons (brown BrdU+ cells) were abundant in TAC-treated mice but absent in controls. Across tissues we saw fewer senescent cells, lower inflammation, stronger muscles (less sarcopenia), better balance, faster gait and improved immune competence – all with no observed side-effects.

8 : 12 – 9 : 38
Because the same ageing drivers initiate age-related diseases, we next asked whether TAC could blunt Alzheimer’s. In a transgenic mouse model we treated from six months (first pathology) for up to six months. TAC reduced amyloid-β plaques and quelled microglial neuro-inflammation.

9 : 38 – 11 : 07
These data suggest we can intercept the root biology of ageing, compress the years of morbidity, and extend health-span (not necessarily lifespan). Imagine being in your 90 s, still playing basketball with your grandchildren.

11 : 07 – 12 : 26
Biology is malleable. If we understand mechanisms, disease can bend to the axe of science, ushering in regenerative rather than reactive medicine—and perhaps a world where people dance through their later decades. Applause.

2. Executive summary

  • Thesis – Ageing is the central risk factor for the major chronic diseases; by targeting its molecular roots we can delay or reverse multiple conditions simultaneously.

  • Key mechanism – Telomerase reverse transcriptase (TERT) maintains telomeres and regulates pro-youth gene networks; TERT levels crash early in ageing.

  • Innovation – Dr DePinho’s team identified a small-molecule activator (TAC) that transiently boosts TERT to youthful levels in every tissue, including the brain.

  • Pre-clinical evidence – In naturally aged mice, intermittent TAC dosing for six months:

    • Re-started adult neurogenesis and improved memory tests.
    • Reduced senescent‐cell burden, inflammation and mitochondrial decline.
    • Strengthened muscle function and immune surveillance.
    • Produced no obvious toxicity.
    • In an Alzheimer’s model, TAC cut amyloid plaques and neuro-inflammation.

  • Vision – Treat ageing upstream, compress morbidity, extend healthy life, and move from “sick-care” to preventive, regenerative medicine.

3. Critique & context

Strengths Limitations / Open questions
Solid biological rationale – Telomerase and telomere attrition are well-validated ageing hallmarks. Supported by extensive genetics; transient telomerase expression has reversed tissue atrophy in earlier mouse studies. Chronic telomerase over-expression can promote tumorigenesis; whether pulsatile pharmacological activation is safe long-term in humans remains untested.
Peer-reviewed data – A 2024 Cell paper reports TAC reversing several ageing hallmarks in aged mice, including neurogenesis and muscle strength, without increasing cancer incidence. (cell.com, pubmed.ncbi.nlm.nih.gov) Provides independent verification, detailed molecular read-outs (DNA methylation, p16 suppression). Mouse models, even aged ones, rarely predict human translational success; lifespan studies under pathogen-free conditions can miss late toxicity.
Blood–brain barrier penetration – unusual for small molecules targeting ageing. Addresses brain ageing and dementia directly—a major unmet need. CNS penetration heightens risk of neuro-psychiatric or off-target effects; safety window in humans unknown.
Intermittent dosing strategy – attempts to mimic youthful TERT pulses while limiting oncogenic risk. Three-times-per-week dosing is patient-friendly. Short half-life reduces cumulative exposure. Need pharmacokinetic/pharmacodynamic data in primates; optimal schedule may differ across tissues and between sexes.
Claims of “no side-effects” – encouraging but preliminary. Six-month mouse study with full necropsy showed no gross toxicity or tumor uptick. (nature.com) Six months in mice ≈ two human years; latent cancers could emerge with longer observation. Regulatory agencies will demand multi-species carcinogenicity trials.
Positioning ageing as a treatable disease Aligns with WHO ICD-11 extension codes and biotech investment trends. Ethical, societal and regulatory frameworks for an “anti-ageing” drug are still nascent; reimbursement models and access remain unresolved.

Additional scientific questions

  1. Mechanism depth – TAC reportedly elevates endogenous TERT transcription via the MEK-ERK-AP-1 axis. But its exact binding target is undisclosed; off-target kinome profiling and chemoproteomics would strengthen confidence.
  2. Cancer surveillance – Telomerase is a near-universal tumor maintenance factor. Although transient up-regulation may be safer than constitutive expression, trials must stratify by baseline clonal hematopoiesis and pre-malignant lesions.
  3. Human biomarkers – Which easily sampled read-outs (e.g., telomere length dynamics in leukocytes, circulating senescence-associated secretory phenotype markers) will track TAC response?
  4. Combination therapy – Ageing is multifactorial; how will TAC integrate with senolytics, NAD+ boosters, or caloric restriction mimetics already entering trials?

Bottom line

Dr DePinho’s talk compellingly frames ageing as a modifiable root cause of disease and presents promising mouse data for a first-in-class TERT activator. The science is exciting, peer-review appears favourable, and the therapeutic concept fits a growing geroscience paradigm. Yet mice are not humans: long-term cancer risk, dosage optimisation, and real-world efficacy remain to be proven. TAC is a step toward true “health-span medicine,” but cautious, rigorously controlled human studies will be essential before we can bank on playing hoops in our 90 s.