talk title: TRCS Aging Theory: The Telomere DNA and Ribosomal DNA Co-Regulation Model for Cell Senescence

speaker: Bilu Huang

date: 2025-10-23

event: Global Summit on Aging & Longevity 2025 | MedGlobal Connect

video: https://www.youtube.com/watch?v=SC19kFTtpZo

paper: https://www.aginganddisease.org/EN/10.14336/AD.2025.0541

LLM-generated summary: The presentation articulates the Telomere DNA and Ribosomal DNA Co-Regulation (TRCS) model of aging, proposed by Bilu Huang in 2021, positing that replicative senescence in adult stem cells—driven by progressive shortening of telomere and ribosomal DNA (rDNA, specifically 45S rDNA) arrays—underlies individual aging through p53 upregulation. This programmed mechanism unifies disparate aging theories, refuting damage accumulation via evidence from killifish lifespan divergence under identical conditions and failed antioxidant interventions, while explaining the 11 hallmarks of aging as downstream p53-mediated effects. Experimental validation includes rDNA knockdown inducing senescence markers (p53, p21, p16, SA-β-gal) and elevated telomere/rDNA arrays in rejuvenated embryonic stem (ES) and induced pluripotent stem (iPS) cells, emphasizing rDNA's greater influence. Therapeutic prospects focus on extending these arrays in situ to evade immune clearance plaguing allogeneic, expanded, or iPS-derived stem cell transplants, contrasting with transient metabolic interventions like rapamycin.

Video description

When killifish species with different lifespans that naturally experience different rainy-season lengths are raised together in the same aquarium, their lifespan differences persist. This indicates that aging beyond sexual maturity is still genetically programmed. Individual aging results from the replicative senescence of adult stem cells, and my research shows that cellular aging is co-regulated by telomeres and rDNA shortening through P53 pathway. In addition, the other 11 classic hallmarks of aging are also downstream markers regulated by the P53 pathway following telomere and rDNA shortening.

Introduction and Declaration of Interest

Hi, hello everyone. Thanks for having us here. And let me do a simple introduction. This is here sitting next to me is Mr. Bilu Huang and he is our chief scientist of Founja Therapeutics and I am the COO and I will be speaking instead of speaking for Bilu Huang and when it comes to the Q&A section, I will be interpreting for Bilu Huang.

And first, thanks for having us on this prestigious summit. So today we are going to introduce why do we age? This is the unified theory of aging proposed by Bilu Huang in 2021. The telomere DNA and ribosomal DNA co-regulation model for cell senescence. It can also be called TRCS model.

First, as the declaration of interest statement, Bilu Huang is the founder and CSO of Fuzhuang Therapeutics, and me, Hu Xiaowen, or you can also call me Claire, I am an employee at Fuzhuang Therapeutics.

Programmed Aging vs. Damage Accumulation

Einstein once said, if you cannot explain it simply, you do not understand it well enough. And as we all know, aging and death are so frightening, so why do we age? Aging is a programmatically controlled program, not the result of random damage accumulation.

The theories of aging are divided into two categories, the damage accumulation theory and the programmed aging theory.

When three killifish strains, one with a three-month lifespan, one with a nine-month lifespan, and one with a 16-month lifespan, they evolved under rainy seasons of corresponding length and they are reared together in the same aquarium, their lifespan difference remained. This shows that post-puberty aging is still genetically programmed because random damage accumulation cannot explain why these three closely related almost identical species differ so dramatically in longevity nor why these differences match the duration of the rainy seasons in their native habitats.

Also, since antioxidants can reduce various types of damage but have failed to extend the lifespan of wild-type mice, this evidence alone is already sufficient enough to refute theory that aging is caused by the accumulation of various random damage.

Replicative Senescence of Adult Stem Cells as Cause of Individual Aging

Individual aging is caused by the replicative senescence of adult stem cells. Replicative senescence is characterized by the phenomenon that with each cell division, daughter cells become older than the mother cell. Specifically, this involves downregulation of overall protein and ATP synthesis rates, while the expression of some proteins is upregulated and others downregulated. This leads to a decline and alteration in cellular function, indicating that cellular senescence is also programmed, continuing until cell ceases division upon reaching the Hayflick limit.

The somatic cells, constituting the various tissues and organs of an individual, are broadly classified into two categories, adult stem cells and functional cells. Although no adult stem cells have been identified in the heart, cardiomyocytes can renew themselves through self-replication. Therefore, cardiomyocytes serve as both adult stem cells and functional cells.

Both adult stem cells and functional cells can be cleared by immune system due to factors such as cellular senescence, genetic mutations, or viral infections. Then, they are replenished through the cell replication and differentiation of adult stem cells.

However, the adult stem cells themselves undergo replicative senescence due to the repeated cell replication. Similarly the functional cells differentiated from aged adult stem cells are also aged functional cells leading to the gradual aging of tissues, organs, systems, and ultimately the entire individual.

Therefore, the fundamental cause of us as the individual aging can be ultimately attributed to the replicative senescence of adult stem cells.

And we can take a look at this figure one. Individual aging results from replicative senescence of adult stem cells. With each replication of somatic stem cells, the daughter cells age slightly compared to the previous generation. Consequently, the functional cells differentiated from this aging somatic stem cells are also aged, like they age after each passage and cell division, leading to the progressive aging of tissues, organs, systems, and ultimately the entire individual.

TRCS Model: Co-Regulation by Telomere and rDNA

The replicative senescence of cells is co-regulated by telomere and rDNA. Telomeres are tandemly repeated multi-copy DNA arrays. Telomere shortening has been proven to act as a constant timer for cell replication and senescence. However, in some cells where telomeres do not shorten, the number of cell replications and lifespan remain limited. Furthermore, it has been observed that maintaining telomere length with telomerase, which increases the number of replications, ultimately does not prevent cells from ceasing replication and dying.

Therefore, besides telomeres, there must be another multi-copy tandemly repeated DNA arrays in the nucleus that serves as a second countdown timer for cell replication and lifespan. Consequently Bilu proposed the telomere DNA and ribosomal DNA co-regulation model for cell senescence. This theory posits that the shortening of telomere and/or rDNA arrays would increase the level of the tumor suppressor protein p53, thereby inducing cellular senescence.

Furthermore, the TRCS theory has been experimentally validated as correct, with rDNA contributing a greater weight to senescence than telomeres.

And here is the TRCS model. In the left, the chromosomes with long arrays of telomeres and rDNA, and p53 is rapidly degraded. p53 levels are low, and the cell is young, youthful. In the right, chromosomes with short arrays of telomere and rDNA and p53 is slowly degraded. p53 levels are high and the cell is aged.

Evidence and Self-Consistency of TRCS Model

The vitality of the theory depends on whether a theory is self-consistent. Since the shortening of telomere DNA and rDNA arrays are the fundamental cause of cell aging and the countdown substance that drives the programmed expression of the gene groups, then the telomere DNA and rDNA that is consumed in somatic cells must be replenished in early embryonic cells or germ cells. Otherwise, life cannot be perpetuated through generations.

Fortunately, there are already enough evidence that have shown that telomere and rDNA consumed in somatic cells can be replenished in early embryonic cells and germ cells.

Stem cells in mice can experience rDNA array shortening due to the mTORC1 pathway activation. Rapamycin, an anti-aging drug, can inhibit mTORC1, thereby suppressing rDNA transcription and cell replication, slowing down replicative cellular senescence and extending the lifespan of mice. It is almost the only most effective anti-aging method or drug that has been proved can extend the lifespan of mice by the most rigorous and authoritative ITP test.

So therefore, from the perspective of first principles, the lifespan of species, any species, is determined by the shortening rate of telomere and rDNA arrays.

Experimental Validation of TRCS

The TRCS model has previously pointed out that the shortening of telomere and/or rDNA arrays leads to an increase in the level of tumor suppressor p53, causing cells to enter a state of senescence and the mechanisms of rejuvenation through the pluripotent reprogramming is due to the significant extension of telomere and rDNA arrays.

Accordingly, we knocked down the 45S rDNA copy number in primary mouse and human cells, and the results showed that aging biomarkers p53, p21, p16, and SA-β-gal were significantly upregulated as expected by Bilu Huang, while telomere length cell viability and cell passage numbers were significantly reduced.

We also tested aging cells and human ES cells and human iPS cells and we found that the telomere length and 45S rDNA copy numbers in aging cells were significantly reduced while those in human ES cells and human iPS cells, that as known as the young cells they were significantly increased.

So this data strongly demonstrates that the rejuvenation mechanism of ES and iPS is not due to the epigenetic reprogramming but because the length of the telomere DNA array and the 45S rDNA array has significantly increased or reset.

The fundamental cause of cellular aging and the Hayflick limit is co-regulated by telomeres and 45S rDNA. And the weight of rDNA in aging is greater than that of telomeres, so it's already validated to be correct by experiments, this aging model.

Unified Explanation of the 11 Hallmarks of Aging

A unified picture explaining the 11 hallmarks of aging. Since the telomeres and the rDNA are universal among all organisms from yeast to mice to humans, therefore the mechanisms of aging across various species have been unified.

Moreover, the 11 other acknowledged well-established hallmarks of aging that has been shown in the very famous paper in Cell journal on Hallmarks of Aging: the Expanding Universe that has been concluded. There are also the downstream consequences mediated by telomere and rDNA shortening through the p53 pathway such as genomic instability, chronic inflammation, epigenetic alteration, and mitochondrial dysfunction.

So they are all the downstream of the upregulation of p53 protein that's caused by the shortening of telomere and rDNA.

The table shows that the 11 hallmarks of aging mediated by telomere and rDNA arrays shortening through p53.

And here the recommended reading that Bilu published the causality of aging hallmarks in Aging and Disease this year.

Summary and Therapeutic Implications

In summary, the ultimate cause of individual aging is the progressive shortening of telomere and rDNA arrays in tissue-resident adult stem cells. In theory, replacing the aged adult stem cells in aging tissues with young adult stem cells can rejuvenate the aged tissues. However, transplanted allogeneic stem cells will be cleared by the immune system within a week. Transplanting autologous stem cells that have been expanded in vitro is also useless as the expansion process induces replicative senescence.

Additionally, transplanting adult stem cells that are derived from iPS cells generated from our cells is also useless because these cells often harbor DNA damage exceeding 70%, which also leads to their immune clearance.

Therefore, these approaches are all not feasible. The only viable solution is to increase the length of telomeres and rDNA arrays in our adult stem cells.

Apart from this, interventions at the metabolic level and in signaling pathways can only slightly extend lifespan come with significant side effects and are impossible to reverse aging that is just like the rapamycin which is the only most effective small molecular anti-aging drugs that have been tested by the ITP program.

If you want to learn and discuss more about aging feel free to contact Bilu Huang. You can email to Bilu or connect with Bilu on LinkedIn or follow him on the X Twitter.

And that's all. Thanks for listening and once again thanks for having us on this a very famous and very informative summit.

Q&A: Differences in Stem Cell Types and Immune Clearance

Anyone have any questions related to the presentation?

I am a little bit confused on the adult stem cells and the stem cells that mentioned that was 70% damaged and wouldn't work. What are the differences?

Oh, so when I say if that's the stem cell that's others other people's stem cell and you have it transplanted into your body and it will be cleared by the immune system within a week and when I said that 70 percent damage and that is according to many papers that says is the adult stem cells derived from iPS cells from our own body also have DNA mutations that it has also exceeded 70%. So it will also ultimately be cleared by the immune system.

And that is exactly why there have already been almost 20 years since the first discovery of iPS cells and it has not been used to replace our aged cells and to extend our lifespan. Just it's the very very important thing is it will be cleared by immune system and also the Sumitomo Pharmaceuticals has recently discussed iPSC cell therapy that has approved by the FDA to treat the Parkinson's disease but we have to be very careful. It also has been used with the immune suppressor, so like rapamycin.

So it also indicates that it will be if we do not use the immune suppressants, it will ultimately be cleared by the immune system, those iPS cell therapy. So is it clear?

Q&A: Ideal Stem Cell Strategy

But then what specifically is the adult stem cells that you refer to that would be ideal, that would work?

So we just mentioned the only viable way is to increase the telomere and rDNA in our own stem cells. That way they have no immune clearance problem and won't be cleared by the immune system. Because the 99% of the biologic therapy medication one and done will fail just because simply because they will be cleared by the immune system like the gene therapy, iPS cell therapy, like that.

Q&A: Strategies to Extend Telomeres and rDNA

So then is there any strategies to improve the telomeres and the rDNA arrays?

Yes, for the telomeres, to extend telomeres, there are telomerase therapies and not the small molecular telomere activators that won't work, but the telomerase therapy, the large molecular as there are already several pipelines of that has that that is being developed around the biotechs are not only by us but also around the globe for example our our friend professor Michael Fossel biotech company Telocyte he is now his company is now developing telomerase therapy to treating the Alzheimer's disease and cardiovascular disease and Rejuvenation Technologies they are using the telomerase therapy to treating some age degenerative disease in the in the lung in the lung and the liver as for the rDNA just how to how to increase rDNA in our stem cells is still in the basic research is still in the basic research period so we need the more fundings and attentions and we need the genius and scientists around the globe, the great minds to put the joint effort to solve the problem, how to increase the rDNA. That will be the final step to increase the rejuvenation.

Q&A: Role of p53 Manipulation

Okay, I have one last question. What about p53? Do you think I think manipulation of the level of p53 can give us the correlated benefits as if you increase the telomeres or the rDNAs, right?

Yes, thank you for the question. And this has been a very broad because people first will be if we can increase rDNA and telomere to decrease the p53 level but can we just directly decrease the p53 level. Because as we know p53, the protein is the master control of the cell senescence, but actually since telomere and rDNA, they are actually a driver or the countdown timer of the genetic program. and the counter of cell division times.

If we just try to rejuvenate aging, aged cells by knocking out the p53 gene or can it continuously inhibiting the p53 protein such as by antibodies, the gene expression profile will not change over time axis and the cell division would go out of control, which will be the same property as cancer cells.

Therefore, we can only downregulate the p53 by lengthening the telomere and rDNA without causing uncontrolled cell division.

Okay. Thank you. That's great.

Thank you. Very good talk. Thank you.

Insights

• Core Intuition: Aging is a genetically programmed countdown timer via shortening of multi-copy DNA arrays (telomeres and 45S rDNA), not stochastic damage; this unifies species-specific lifespans and explains replenishment in germline/embryonic cells for generational continuity.
• Mechanistic Insight: Shortening of telomere/rDNA arrays slows p53 degradation, elevating p53 to trigger senescence; rDNA exerts greater influence, validated by knockdown upregulating p53/p21/p16/SA-β-gal and reduced proliferative capacity, while ES/iPS rejuvenation resets these arrays (not mere epigenetics).
• Trick for Validation: Self-consistency test—somatic consumption must reset in germline (observed); rapamycin inhibits mTORC1 to suppress rDNA transcription/replication, slowing senescence (ITP-validated lifespan extension in mice).
• Main Concepts: TRCS model integrates 11 hallmarks (e.g., genomic instability, inflammation) as p53-downstream effects; therapeutic pivot to in situ array extension avoids immune clearance of transplants (allogeneic <1 week; iPS-derived >70% DNA damage; expanded autologous senesce).
• Key Caution: Direct p53 inhibition risks oncogenesis by decoupling from replication timer; telomerase gene therapies (e.g., Telocyte Biotech) viable for telomeres, rDNA extension needs R&D.

Transcription error corrections

• Names/Company: "Bi Lu Huang" consistently transcribed as such; best guess "Bilu Huang" (common phonetic rendering; matches publication credits). Company: "Fuzhou Therapeutics", "Fujong Therapeutics", "Houdon Therapeutics" → unified to "Fuzhuang Therapeutics". Speakers: "Hu Xiaowen/Claire" clear.
• Species: "killfish" → "killifish" (Nothobranchius genus, standard aging model).
• Biology Terms: "half-lake limit" → "Hayflick limit". "rDNA" → "ribosomal DNA", specified as "45SR DNA"/"45SRDNA" → "45S rDNA" (standard pre-rRNA gene cluster). "Reprimexin"/"rapimethin"/"ripamycin" → "rapamycin". "ITP test" → "ITP" (NIA Interventions Testing Program).
• Other: "raining seasons" → "rainy seasons" (ecological context). "mTOR1 IV" → "mTORC1 pathway". "otologist stem cells" → "autologous". "smithomal pharmaceuticals" → "Sumitomo Pharmaceuticals". "michael fossils" → "Michael Fossel" (telomerase researcher). "Telesio"/"Teleside" → "Telocyte" (Fossel's venture). "Rejuvenative Technologies" → "Rejuvenation Technologies"

See also

• longevity