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11:33 < hprmbridge> marshallsito> A bridge developer who’s been working on cross-chain messaging, asset transfers and all the weird edge cases that show up when two chains don’t agree on anything. Most of my day is spent making sure users can move value safely without needing to understand consensus, finality or why block timestamps lie. My biggest project this past year was upgrading a multi-chain bridge that kept hitting
11:33 < hprmbridge> marshallsito> reliability issues during high-load windows. I redesigned the message verification layer using a hybrid light-client + attestation model, added per-chain failover logic and tightened the fraud-proof window to catch spoofed packets faster. After rollout, failed transfers dropped ~58%, average confirmation time improved ~35% and gas costs for relay operations went down ~20% across the supported
11:33 < hprmbridge> marshallsito> chains. If you’re into cross-chain systems, messaging layers or making bridges actually trustworthy, feel free to reach out. Always happy to talk shop with fellow builders.
11:34 < hprmbridge> kanzure> banned.
11:34 < hprmbridge> kanzure> No really, who wants to setup anti-spam on discord for me
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13:00 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=812b7fc5 Bryan Bishop: several more longevity TODOs >> 
13:24 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=cad7d186 Bryan Bishop: high oxygen transport via EPOR mutation >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
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13:57 < fenn> did tessier sign us up to some spam list?
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13:59 < fenn> this "recruit me i'm a pro" stuff started at exactly the same time as he was complaining
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15:39 < hprmbridge> kanzure> "Elevated DNA damage without signs of aging in the short-sleeping Mexican cavefish" https://elifesciences.org/articles/99191
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17:33 < hprmbridge> kanzure> Hello @biluhuang_09127
17:34 < hprmbridge> kanzure> we are interested in longevity interventions. Mainly transgenic though! It is much easier at the embryo stage.
17:35 < L29Ah> kanzure is obsessed with transgenic ones, pretty sure lots of others care about the living as well :P
17:40 < hprmbridge> biluhuang_09127> Hi everyone! I'm Bilu Huang, a theoretical biologist from China. I've been researching the biology of aging, age-related diseases and life extension for over 30 years. My work focuses on the "mechanisms of biological aging," and I recently proposed a model called TRCS, which attempts to explain how telomeres and ribosomal DNA co-regulate cellular senescence. If you're interested in this topic:
17:40 < hprmbridge> biluhuang_09127>
17:40 < hprmbridge> biluhuang_09127> Paper here: https://www.aginganddisease.org/EN/10.14336/AD.2025.0541
17:40 < hprmbridge> biluhuang_09127>  My presentation at the 2025 Global Summit on Aging & Longevity in Tokyo: https://www.youtube.com/watch?v=SC19kFTtpZo&t=1164s
17:40 < hprmbridge> biluhuang_09127>  More about our institute's work: https://aging.biluhuang.com/
17:40 < hprmbridge> biluhuang_09127>
17:40 < hprmbridge> biluhuang_09127> Glad to join this longevity discussion group! Looking forward to exchanging ideas and hearing about your research or interests. What areas of longevity are you all focusing on currently? 😊
17:40 < hprmbridge> kanzure> L29, it is much harder to solve for adults. It is better to not have aging at all. Fixing an aged adult is very hard.
17:44 < hprmbridge> biluhuang_09127> The summary of the TRCS Model is as follows: My research shows that aging is essentially a genetic program driven by telomeres and/or rDNA shortening through the p53 pathway, rather than the accumulation of damage. Individual aging results from replicative senescence of adult stem cells; and that cellular senescence is co-regulated by telomeres and rDNA through the p53 pathway. Moreover, the 11
17:44 < hprmbridge> biluhuang_09127> other classic hallmarks of aging are downstream events regulated by p53 upregulation after telomere and rDNA shortening. From the perspective of first principles, the lifespan of a species is determined by the shortening rate of telomeres and rDNA arrays. 😊
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17:46 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=8ca3410e Bryan Bishop: transcript: bilu huang 2025 TRCS talk at medglobal >> http://diyhpl.us/diyhpluswiki/transcripts/trcs-aging-theory-bilu-huang-2025/
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17:48 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=dd60fd52 Bryan Bishop: add link to paper >> http://diyhpl.us/diyhpluswiki/transcripts/trcs-aging-theory-bilu-huang-2025/
17:48 < hprmbridge> kanzure> @biluhuang_09127 I have added a transcript of your video here, hopefully there are no major errors in my speech-to-text https://diyhpl.us/wiki/transcripts/trcs-aging-theory-bilu-huang-2025/
17:50 < fenn> @biluhuang_09127 i appreciate what you are doing, personally i don't want to die. i am curious how you resolve the theoretical conflict between genetically programmed aging and apparently effective physical interventions such as blood plasma dilution / heterochronic parabiosis
17:51 < fenn> is aging actually two or more phenomena?
17:52 < MuaddibLLM> [gemini-3-pro-preview] Based on the TRCS transcript, she lumps metabolic/signaling interventions (like rapamycin) as incapable of reversing aging; she'd likely view plasma dilution as just temporarily scrubbing the downstream p53/SASP inflammation without actually rewinding the rDNA/telomere hardware clock.
17:53 < L29Ah> fenn: it is complicated
17:54 < L29Ah> MuaddibLLM: what are the major theories of aging?
17:54 < MuaddibLLM> checking the current consensus on aging theory classifications...
17:54 < MuaddibLLM> [gemini-3-pro-preview] It's mostly a cage match between **Damage/Error** (entropy, somatic mutations, ROS) and **Programmed** (telomere/rDNA clocks like TRCS), though **Antagonistic Pleiotropy** (Blagosklonny's "hyperfunction") remains the best explanation for *why* natural selection treats your post-reproductive body like disposable trash.
17:55 < hprmbridge> kanzure> from the wiki page: During aging and runaway aging, the genome loses copies of ribosomal RNA (rRNA) because of excision, DNA damage repair, etc. rRNA is apparently stored on 13p12, 14p12, 15p12, 21p12, 22p12. There are several hundred copies in a healthy non-aged adult genome. One obvious thing to do would be to add extra copies of rRNA genes throughout the genome in different locations, and
17:55 < hprmbridge> kanzure> ensure that if needed they can be used (not under heterochromatin silencing or the silencing can be turned off when the cell needs these other rRNA copies).
17:56 < hprmbridge> biluhuang_09127> Thank you. I'm sorry, this is my first time joining a Discord group chat, and I'm not familiar with the operations yet, so my replies might be a bit slow.
17:57 < hprmbridge> biluhuang_09127> Thank you
17:57 < fenn> this is a bit of a strange chat because we have a bridge to the libera IRC network as well
17:57 < fenn> so some discord functions might not work as expected, such as notifications, message edits, etc
17:58 < fenn> i see your messages as plain text that looks like: hprmbridge> biluhuang_09127> Thank you
17:59 < fenn> also a lot of noise from bots that is hopefully useful sometimes...
18:00 < hprmbridge> biluhuang_09127> The Essence of Aging is a Program
18:00 < hprmbridge> biluhuang_09127> Aging theories can be broadly divided into two categories: the damage accumulation theory (or entrophy aging theory or wear-and-tear theory) and the programmed theory. The entropy theory of aging also belongs to the damage accumulation theory.
18:00 < hprmbridge> biluhuang_09127>
18:00 < hprmbridge> biluhuang_09127> The following evidence indicates that the essence of aging is a program:
18:00 < hprmbridge> biluhuang_09127>
18:00 < hprmbridge> biluhuang_09127> 1.1 Each species has a relatively fixed timetable for development, maturation, aging, and death. Human infants begin to grow deciduous teeth at 6 months after birth, start replacing them with permanent teeth at around 6 years old, and begin to grow beards at approximately 16 years old, etc. Silkworms hatch from eggs into small larvae, undergo several molts, then pupate, break out of the cocoon as
18:00 < hprmbridge> biluhuang_09127> moths, mate, lay eggs, and then die (Figure 1). Therefore, it is evident that the development, maturation, aging, and death of an individual are essentially a genetic program.
18:00 < hprmbridge> biluhuang_09127>
18:00 < hprmbridge> biluhuang_09127> 1.2 When three killifish strains with lifespans of 3 months, 9 months, and 16 months, adapted to different rainy season lengths, are raised together in the same artificial pond, their lifespan differences persisted. This indicates that post-sexual maturation, aging is still controlled by a program, as random damage accumulation cannot explain why the lifespans of these three congeneric killifish
18:00 < hprmbridge> biluhuang_09127> with extremely similar body structures differ so greatly (Figure 2), and precisely coincide with the length of the rainy season [1].
18:00 < hprmbridge> biluhuang_09127>
18:00 < hprmbridge> biluhuang_09127> 1.3 Sublethal doses of radiation can increase DNA and protein damage, but also extend the lifespan of fruit flies, houseflies, rats, and mice [2-5]. This indicates that aging cannot be caused by damage accumulation.
18:01 < hprmbridge> biluhuang_09127> The Manifestation of Aging Is a Process of Progressive Decline and Alteration in Physiological Function
18:01 < hprmbridge> biluhuang_09127>
18:01 < hprmbridge> biluhuang_09127> Over time, the overall synthesis rates of proteins and ATP in cells gradually decline, while gene expression profiles also continuously change. Therefore, aging can be defined as the process in which the physiological functions of cells and individuals progressively decline and change over time. For example, compared to young rats, the synthesis of rRNA, mRNA, and proteins in lymphocytes of old
18:01 < hprmbridge> biluhuang_09127> rats is downregulated by nearly 20-fold. In rat liver tissue, ATP levels were measured as 0.24±0.06 nmol/L in the young group, 0.19±0.10 nmol/L in the adult group, and 0.06±0.03 nmol/L in the old group [37], leading to a progressive decline in physiological function. During aging, hematopoietic stem cells exhibit approximately 1,500 genes downregulated and another 1,500 genes upregulated [17]. In
18:01 < hprmbridge> biluhuang_09127> liver cells, alpha-fetoprotein is expressed during the fetal stage, its expression ceases from birth to adulthood, and albumin is expressed instead. In old age, albumin expression gradually declines, and another protein begins to be expressed, resulting in changes in physiological function. It is evident that the essence of aging is a genetic program driven by timing substances, which also
18:01 < hprmbridge> biluhuang_09127> underlies the nonlinear changes of aging and the onset of various degenerative diseases.
18:01 < hprmbridge> biluhuang_09127> It is noteworthy that when normal liver cells transform into liver cancer cells, they retain the characteristics of liver cells but re-express alpha-fetoprotein. This indicates that the genetic program of aging is reversible, whereas cell differentiation is irreversible.
18:03 < hprmbridge> biluhuang_09127> Aging Is a Physiological Process
18:03 < hprmbridge> biluhuang_09127>
18:03 < hprmbridge> biluhuang_09127> Regarding whether aging is a physiological process or a disease, this debate resembles the endless argument over whether the chicken or the egg came first. First, we need to clarify the sequence of events. Since chickens originated from gradual genetic mutations in avian germ cells, and eggs are the products of germ cells, it follows that the egg came first.
18:03 < hprmbridge> biluhuang_09127> I believe it can be stated with absolute certainty that aging is a physiological process. The reasoning is straightforward and supported by the following points:
18:03 < hprmbridge> biluhuang_09127>
18:03 < hprmbridge> biluhuang_09127> Not everyone contracts the same disease, but everyone undergoes aging.
18:03 < hprmbridge> biluhuang_09127>
18:03 < hprmbridge> biluhuang_09127> Raising animals in a clean environment can prevent infectious diseases, but it cannot prevent aging.
18:03 < hprmbridge> biluhuang_09127>
18:03 < hprmbridge> biluhuang_09127> Aging is an orderly genetic process, whereas diseases occur randomly.
18:03 < hprmbridge> biluhuang_09127>
18:03 < hprmbridge> biluhuang_09127> While aging increases susceptibility to diseases, this is not a direct effect of aging but rather an indirect one. For example, the aging of the immune system leads to a decline and dysregulation of immune function, increasing the likelihood of infectious diseases, tumors, or autoimmune disorders. Additionally, aging reduces the efficiency of clearing misfolded proteins, which is one of the
18:03 < hprmbridge> biluhuang_09127> primary causes of neurodegenerative diseases
18:07 < fenn> i think we agree on most of that
18:08 < fenn> re 1.3, radiation hormesis is a process where cellular damage and oxidative stress from radiation upregulates repair genes and antioxidant production, and can result in less accumulated damage as a result
18:08 < fenn> but that is somewhat of a distraction i think
18:09 < fenn> cells can be de-differentiated to any stage of the lifecycle with OSKM yamanaka factors
18:09 < fenn> what i don't understand is why blood plasma dilution should alter any of this program
18:11 < hprmbridge> biluhuang_09127> 22 compelling pieces of evidence refuting the idea that aging is caused by damage accumulation, entropy increase, or wear and tear
18:11 < hprmbridge> biluhuang_09127> https://cdn.discordapp.com/attachments/1064664282450628710/1447410192231956612/22_compelling_pieces_of_evidence_refuting_the_idea_that_aging_is_caused_by_damage_accumulation_entropy_increase_or_wear_and_tear.txt?ex=69378549&is=693633c9&hm=6ccbb888d81a74db2ad383b389585846baf8703fe4ded75fddba3d13c358ac07&
18:11 < hprmbridge> biluhuang_09127> Huang, Bilu and Hu, Xiaowen, Programmed Aging Theory Defeats Damage Accumulation Theory of Aging (July 28, 2025). Available at SSRN: https://ssrn.com/abstract=5368732
18:19 < hprmbridge> kanzure> Are there any other transgenic or germline interventions besides "add more copies of ribosomal rRNA" that TRCS predicts?
18:20 < fenn> https://news.berkeley.edu/2020/06/15/diluting-blood-plasma-rejuvenates-tissue-reverses-aging-in-mice/
18:20 < L29Ah> http://aging.biluhuang.com/ cool huh
18:22 < hprmbridge> biluhuang_09127>  https://cdn.discordapp.com/attachments/1064664282450628710/1447413050721177792/14.png?ex=693787f2&is=69363672&hm=e111c667a1287708039bac9121927e4fe2d53597d1ea7b93f0871e9e237b66fb&
18:23 < hprmbridge> biluhuang_09127> 15. Injection of Young Blood
18:23 < hprmbridge> biluhuang_09127>
18:23 < hprmbridge> biluhuang_09127> It doesn't work, as it hasn't been shown to extend mouse lifespan. In 1958, Hayflick and Moorhead mixed male fibroblasts that had divided 40 times with normal female fibroblasts that had divided 10 times, and also used cells cultured alone as a control. When the cells in the individual cultures stopped dividing, they examined the mixed cultures and found only female fibroblasts remained. This
18:23 < hprmbridge> biluhuang_09127> experiment suggests that cell division cessation is determined by factors within the cells themselves. This experiment suggests that young blood has no life-extending effect. Furthermore, blood transfusions can reduce the activity of the host's macrophages and natural killer cells, increasing tumor recurrence rates. Plasma transfusions have the most significant effect on suppressing the immune
18:23 < hprmbridge> biluhuang_09127> system, followed by white blood cell transfusions. The typical lifespan of mice is 2.5 years (30 months). A 2014 research paper compared the repeated injections of young plasma into old mice with a control group that received saline. The median lifespan of the control group was 27 months, while that of the plasma-treated group was 26.4 months. Not only did it not extend lifespan, it actually
18:23 < hprmbridge> biluhuang_09127> shortened it slightly.
18:23 < hprmbridge> biluhuang_09127>
18:23 < hprmbridge> biluhuang_09127> [1] Dmytro S, Olexiy B, et al. (2014). Aged Mice Repeatedly Injected with Plasma from Young Mice: A Survival Study. BioResearch Open Access, 3:225-232
18:26 < hprmbridge> biluhuang_09127> 🚫 After systematically reviewing 26 all mainstream anti-aging methods– from antioxidants and senolytics to reprogramming and metabolic interventions., I found most are fundamentally flawed or have limited effects.
18:26 < hprmbridge> biluhuang_09127>
18:26 < hprmbridge> biluhuang_09127> The contradictions are undeniable — if these approaches worked, why do they fail to deliver significant lifespan extension?
18:26 < hprmbridge> biluhuang_09127>
18:26 < hprmbridge> biluhuang_09127> That’s why I proposed the TRCS model — a new paradigm to explain aging through telomere DNA and ribosomal DNA co-regulation.
18:26 < hprmbridge> biluhuang_09127>
18:26 < hprmbridge> biluhuang_09127> Read my full critical analysis here:
18:26 < hprmbridge> biluhuang_09127> https://aging.biluhuang.com/critical-analysis
18:26 < hprmbridge> biluhuang_09127>
18:26 < hprmbridge> biluhuang_09127> I welcome your thoughts, critiques, and shares. Let’s rethink aging together.
18:26 < fenn> i'm not sure if saline is a good control when allegedly the saline dilution itself is therapeutic
18:26 < hprmbridge> biluhuang_09127> The life-extending effect is very slight.
18:28 < hprmbridge> biluhuang_09127> A similar nationwide movement occurred in China in the 1970s, with people believing that injecting themselves with youthful chicken blood could prolong life, reverse aging, and cure all diseases. However, after a few years, people realized the truth, and the method faded away.
18:35 < hprmbridge> biluhuang_09127> Currently, the most effective life-extending method for WT mice is telomerase therapy, which targets the telomeres in the TRCS model. When we can, we will be able to completely reverse aging, replace organ transplantation, significantly extend lifespan, and return to our vibrant youth.
18:35 < hprmbridge> biluhuang_09127>
18:35 < hprmbridge> biluhuang_09127> Maria Blasco' team have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1‐ and 2‐year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers
18:35 < hprmbridge> biluhuang_09127> of aging. Importantly, telomerase‐treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase‐treated mice, both at 1‐year and at 2‐year of age, had an increase in median lifespan of 24 and 13%, respectively. Telomerase gene
18:35 < hprmbridge> biluhuang_09127> therapy in adult and old mice delays aging and increases longevity without increasing cancer.
18:35 < hprmbridge> biluhuang_09127>
18:35 < hprmbridge> biluhuang_09127> https://pubmed.ncbi.nlm.nih.gov/22585399/
18:36 < hprmbridge> biluhuang_09127> I believe that extending telomeres would have a more pronounced lifespan-extending effect in non-human primates, cats, dogs, and humans, as mice naturally have very long telomeres.
18:36 < hprmbridge> biluhuang_09127>
18:36 < hprmbridge> biluhuang_09127> Increasing telomere length can significantly increase the number of cell divisions and reduce markers of aging [52-53], an effect that other aging interventions cannot achieve, indicating that telomere shortening is one of the fundamental causes of cellular aging.
18:37 < hprmbridge> biluhuang_09127> Another drug that showed the best life-extending effect in ITP testing was rapamycin. Rapamycin's anti-aging and life-extending effects ultimately stem from inhibiting rDNA transcription, that is, preventing rDNA copy number loss. This is consistent with my TRCS model.
18:40 < fenn> what do you think of david sinclair's experiments with OSK epigenetic "reprogramming" that also induces TET1 and lengthens telomeres?
18:42 < hprmbridge> biluhuang_09127> Epigenetic changes are not the cause of aging but rather a result of the shortening of telomere and rDNA arrays through p53 pathway.
18:42 < hprmbridge> biluhuang_09127>
18:42 < hprmbridge> biluhuang_09127> 3.3 Epigenetic Alterations
18:42 < hprmbridge> biluhuang_09127>
18:42 < hprmbridge> biluhuang_09127> As age increases, epigenetic features such as DNA methylation patterns and histone modifications undergo changes, which affect gene expression and cellular functions.
18:42 < hprmbridge> biluhuang_09127>
18:42 < hprmbridge> biluhuang_09127> However, age-related epigenetic changes are also regulated by telomeres and rDNA [26-28]. P53 can bind to the promoter of the DNMT1 gene to mediate epigenetics [29]. Therefore, epigenetic changes are not the cause of aging but rather a result of the shortening of telomere and rDNA arrays. Thus, anti-aging approaches that solely target epigenetic modifications are not viable. For example, partial
18:42 < hprmbridge> biluhuang_09127> reprogramming (expressing Oct4, Sox2, Klf4, and C-myc) in 12-month-old wild-type mice did not extend lifespan [78]. The median lifespan of partially reprogrammed wild-type mice only increased by 12%, which is less effective than small-molecule anti-aging drugs [79]. The slight increase in lifespan may be related to the cell regeneration-promoting properties of the Yamanaka factors Oct4, Sox2,
18:42 < hprmbridge> biluhuang_09127> Klf4, and doxycycline used in reprogramming. For instance, promoting angiogenesis can significantly extend the mouse lifespan [80]. After partial reprogramming was completed, it was found that telomeres did not lengthen or were slightly shortened, aging markers began to accumulate again, and the epigenetic age returned to the state before reprogramming [81].
18:42 < hprmbridge> biluhuang_09127> Growth hormone can reverse the DNA methylation clock [82], but it shortens the lifespan of mice. Rudman's growth hormone supplementation experiment in elderly individuals found that growth hormone could increase muscle mass and thicken the skin in individuals aged 60-80, making them appear 10-20 years younger. However, follow-up studies revealed that elderly individuals who received long-term
18:42 < hprmbridge> biluhuang_09127> growth hormone supplementation not only failed to extend their lifespan but also experienced accelerated aging. A 60-year-old individual who received gene therapy for growth hormone-releasing hormone (GHRH) showed a reversal in physiological age, with a 28.6-year reduction in PhenoAge clock age and a 6-year reduction in epigenetic age, but their telomere age was 7 months older than that of peers
18:42 < hprmbridge> biluhuang_09127> [83].
18:43 < hprmbridge> biluhuang_09127> 2. Cell Reprogramming
18:43 < hprmbridge> biluhuang_09127>
18:43 < hprmbridge> biluhuang_09127> It won't work. Cellular reprogramming includes “pluripotent reprogramming,” “partial reprogramming,” and “direct reprogramming.” In pluripotent reprogramming, somatic cells are completely reverted to a pluripotent state; in partial reprogramming, these cells may be rejuvenated but do not lose their cellular identity; and in direct reprogramming (transdifferentiation), somatic cells are directly
18:43 < hprmbridge> biluhuang_09127> converted into another type of differentiated cell.
18:43 < hprmbridge> biluhuang_09127> The iPS cells generated by pluripotent reprogramming, according to the “Telomere DNA and Ribosomal DNA co-regulation model for cell senescence,” have been found to have significantly increased telomere length and rDNA array length compared to senescent somatic cells, indicating that the cellular age is reversed to 0 years. However, iPS cells or adult cells differentiated from iPS cells can also be
18:43 < hprmbridge> biluhuang_09127> subject to immune rejection. For example, on May 13, 2011, Nature reported that American scientists transplanted mouse iPS cells or adult cells differentiated from iPS cells into mice from which the cells were derived. It was originally thought that there would be no rejection due to the identical genetic background, but the mice rapidly rejected the transplanted cells [1]. On August 11, 2022, a
18:43 < hprmbridge> biluhuang_09127> paper published in Nature Genetics confirmed that nearly three-quarters of iPS cell lines have severely damaged DNA. Moreover, allogeneic iPS cells with the same homozygous human leukocyte antigen (HLA) haplotype as the patient can still cause immune rejection [2], indicating that even with the same HLA, allogeneic stem cells will still be rejected.
18:44 < hprmbridge> biluhuang_09127> In 2024, Deng Hongkui and others published a paper in Cell on the transplantation of islets derived from chemically induced pluripotent stem cells (CiPSCs) for the treatment of type 1 diabetes. The use of immunosuppressive agents indicates that small molecule reprogramming can also be rejected [3]. The original text is as follows: Before CiPSC-islets transplantation, the patient was maintained on
18:44 < hprmbridge> biluhuang_09127> immunosuppressive therapy with tacrolimus (2-2.5 mg/day), mycophenolate mofetil (1 g/day) and methylprednisolone tablets (8 mg/day) due to liver transplantation. For CiPSC-islets transplantation, Basiliximab (20 mg) was used for induction therapy on day 0 and day 4. Etanercept was administrated intravenously on day 0 (50 mg) and subcutaneously on day 3, day 7 and day 10 (25 mg) to alleviate
18:44 < hprmbridge> biluhuang_09127> inflammatory reactions. For maintenance therapy, the previously described immunosuppressive maintenance regimen for liver transplantation was continued. Cefazolin Sodium was administered for infection prophylaxis during the perioperative period.
18:44 < hprmbridge> biluhuang_09127> Partial reprogramming is also not viable because it has been found that the telomere length does not increase or even slightly decreases in partial reprogramming [4], and it is estimated that the length of the rDNA array does not increase either. After the cessation of Yamanaka factor expression, the epigenetic age quickly reverts to the previous state, and aging symptoms accumulate rapidly.
18:44 < hprmbridge> biluhuang_09127> Multiple cycles of treatment only extended the lifespan of progeroid mice by 30%, but failed to extend the lifespan of wild-type mice, indicating that partial reprogramming did not reverse the underlying mechanisms of aging. If in vivo reprogramming is excessive, it can cause mouse death or the formation of iPS cells and fatal teratomas derived from iPS cells. Partial reprogramming uses
18:44 < hprmbridge> biluhuang_09127> doxycycline, which is mentioned below to significantly extend the lifespan of Caenorhabditis elegans and mice. The earliest in vivo partial reprogramming experiments were conducted in 2016, and to date, they have not extended the lifespan of normally aging mice. In 2016, Cell reported that cyclic transient expression of the four Yamanaka factors—Oct4, Sox2, Klf4, and c-Myc (abbreviated as OSKM)—in
18:44 < hprmbridge> biluhuang_09127> mice significantly extended the lifespan of progeroid mice, but did not extend the lifespan when OSKM was induced in normally aging mice (12 months old) [5]. Altos Labs, founded with $3 billion in investment from the world's richest man Jeff Bezos and Yuri Milner, reported in September 2024 that partial reprogramming only increased the median lifespan of wild-type mice by 12%, which is not as
18:44 < hprmbridge> biluhuang_09127> effective as small molecule anti-aging drugs. It can be said that the path of partial reprogramming has been declared a failure [6].
18:44 < hprmbridge> biluhuang_09127>
18:44 < hprmbridge> biluhuang_09127> Direct reprogramming has not been found to reverse the aging phenotype [7].
18:45 < fenn> why haven't efforts to directly lengthen telomeres been successful? BioViva has been trying for over a decade
18:47 < hprmbridge> biluhuang_09127> Coincidentally, I was debating with David Sinclair on Twitter yesterday. He cited his paper published in Cell on reversing monkey vision through partial epigenetic reprogramming, but the results proved my analysis right: the effect of partial epigenetic reprogramming is temporary.
18:47 < hprmbridge> biluhuang_09127> https://x.com/BrazzaBio/status/1997321134778245190?s=20
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18:49 < hprmbridge> biluhuang_09127> Furthermore, partial reprogramming does not extend the lifespan of wild-type mice [doi: 10.1016/j.cell.2016.11.052] or only increases their median lifespan by 12% [doi: 10.1126/scitranslmed.adg1777], which is less effective than some small-molecule anti-aging drugs. This is a study published in a Science sub-journal by Altos Labs, a company invested in by Bezos, on the lifespan extension effects
18:49 < hprmbridge> biluhuang_09127> of partial reprogramming.
18:49 < hprmbridge> biluhuang_09127>
18:49 < hprmbridge> biluhuang_09127> The 12% increase in median lifespan is likely unrelated to induced partial reprogramming, but rather attributed to the antibiotic—doxycycline.
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18:50 < hprmbridge> biluhuang_09127> Currently, many people do not accept the programmed theory of aging and, therefore, do not support the telomere theory of aging. Instead, they believe in the damage accumulation theory, leading to significant investments in areas such as repairing mitochondrial damage and protein misfolding. The informational theory of aging also falls under the damage accumulation theory, which is why a lot of
18:50 < hprmbridge> biluhuang_09127> funding is directed toward epigenetic reprogramming. As a result, investments in lengthening telomeres for anti-aging purposes remain scarce.
18:52 < hprmbridge> biluhuang_09127> Just like my friend Michael's biotech telocyte, which is developing telomerase therapy to treat Alzheimer's disease. However, because most people believe that aging is caused by the accumulation of damage, capital is not being invested in telomerase therapy to treat Alzheimer's disease by lengthening telomeres.
18:52 < hprmbridge> biluhuang_09127>
18:52 < hprmbridge> biluhuang_09127> In the treatment of Alzheimer's disease, the belief that the accumulation of misfolded proteins is the cause has led to massive investments in research aimed at clearing amyloid plaques. However, these funds have essentially been wasted. Recently, it was discovered that an antibody can efficiently remove amyloid proteins, yet it still fails to significantly improve AD symptoms. From 2000 to 2017,
18:52 < hprmbridge> biluhuang_09127> 33 leading pharmaceutical companies collectively invested over $600 billion in AD-related research, with an average daily R&D expenditure of around $1 billion. In 2017 alone, R&D spending reached $71.4 billion. Nevertheless, numerous clinical trials for drugs targeting amyloid clearance have ended in failure. 😢
18:53 < hprmbridge> biluhuang_09127> Accumulated damage fundamentally cannot be repaired with medication, but if one is young enough and lives long enough, it can eventually return to normal. For instance, when I was 15, I went to dig in an orchard during winter. One of my hands suffered frostbite, causing the skin to crack and leaving a scar, but now the scar is barely visible. Additionally, research has found that infants can
18:53 < hprmbridge> biluhuang_09127> regenerate severed fingertips, newborn mice within the first week can regenerate heart tissue, and youthful macrophages can gradually shrink atherosclerotic plaques.
18:53 < hprmbridge> biluhuang_09127>
18:53 < hprmbridge> biluhuang_09127> In this way, the damage seen in the lab or in the tissue clinically is the result of aging, not the cause. Because as long as the individual organ tissues and cells are young enough, they can repair the damage to a harmless level.
18:53 < hprmbridge> biluhuang_09127>
18:53 < hprmbridge> biluhuang_09127> So intervening and repairing the damage yourself is useless. like many's attempt to treat AD or PD by clearing ab or tau protein.
18:53 < hprmbridge> biluhuang_09127>
18:53 < hprmbridge> biluhuang_09127> Therefore, we should extend telomeres and rDNA to reverse cellular aging, cure degenerative diseases, and significantly extend lifespan.
19:00 < fenn> ah i missed the "critical analysis" link. also, i was confused about the function of TET1 and thought it had something to do with telomeres
19:00 < hprmbridge> biluhuang_09127> https://aging.biluhuang.com/critical-analysis
19:08 < fenn> would "add more copies of ribosomal rRNA" even work? chatgpt says p53 is activated by genome instability -
19:08 < fenn> "Both telomere dysfunction and rDNA/nucleolar stress generate persistent DDR/nucleolar signals that converge on p53 stabilization (via post‑translational phosphorylation and MDM2 inhibition)."
19:08 < fenn> i'm sorry i don't know much about p53 so i have to read up on this
19:09 < fenn> why not express MDM2?
19:10 < fenn> DDR = DNA damage response
19:14 < hprmbridge> kanzure> 'Short telomeres generate chronic, non-repairable DDR signalling that keeps p53 transcriptionally active indefinitely' hmmm
19:14 < hprmbridge> kanzure> Quote is from https://gnusha.org/logs/2025-12-05.log
19:16 < fenn> "rDNA repeats are fragile and subject to copy‑number changes, recombination, transcriptional perturbation, or replication stress." (chatgpt)
19:16 < hprmbridge> biluhuang_09127> https://www.aginganddisease.org/EN/10.14336/AD.2025.0541#17 3.1 Genomic instability
19:17 < hprmbridge> kanzure> "DNA damage responses and p53 in the aging process" https://ashpublications.org/blood/article/131/5/488/104405/DNA-damage-responses-and-p53-in-the-aging-process
19:17 < fenn> i mean p53 is useful for stopping occasional wild mutant cancer cells, but maybe there's just too much of it from a whole system perspective
19:17 < hprmbridge> kanzure> Chronic p53 is different from transient p53 activation
19:19 < hprmbridge> biluhuang_09127> The p53 protein serves as the master regulator of cellular senescence.
19:19 < hprmbridge> biluhuang_09127>
19:19 < hprmbridge> biluhuang_09127> In young and aging cells, the arrangement and copy number of various genes on chromosomes generally do not change over time. So, what drives the fixed genes to undergo programmed expression (sequential expression) along the timeline?
19:19 < hprmbridge> biluhuang_09127>
19:19 < hprmbridge> biluhuang_09127> Approximately one-tenth of human gene promoters contain P53 binding sites and can thus be classified as P53-responsive genes [23]. P53 not only downregulates the overall rate of protein synthesis but also acts as a transcription factor capable of simultaneously silencing and activating numerous genes, thereby influencing various aging markers. Therefore, as long as the level of P53 gradually
19:19 < hprmbridge> biluhuang_09127> increases, the overall rate of protein synthesis will gradually decrease, and some genes will be specifically up- or downregulated, leading to both functional decline in cells and a programmatic pattern of gene expression. Due to the differently programmed genetic programs in cells of various differentiation types, there are distinct gene expression patterns during the aging process. For example,
19:19 < hprmbridge> biluhuang_09127> in aging hematopoietic stem cells, approximately 1,500 genes show significant upregulation or downregulation with increasing age [24].
19:20 < hprmbridge> kanzure> Copy number can also be different between different somatic cells ... Even different between dizygotic twins.
19:21 < hprmbridge> biluhuang_09127> The increase in p53 levels is caused by telomere and rDNA shortening. Therefore, the fundamental cause of cellular senescence lies in telomere and rDNA shortening.
19:21 < hprmbridge> biluhuang_09127>  https://cdn.discordapp.com/attachments/1064664282450628710/1447427910624350219/3-1.png?ex=693795c9&is=69364449&hm=225820752c1d68a5365c3e26da91894db7fa51fee6c2e38828389d7c1b8f79ee&
19:22 < hprmbridge> biluhuang_09127> Aging is not related to the number of p53 gene copies, but is associated with the concentration gradient changes of P53 protein over the time axis.
19:22 < hprmbridge> biluhuang_09127>
19:22 < hprmbridge> biluhuang_09127> A higher number of p53 gene copies does not mean a higher level of P53 protein. For example, in yeast cells with 40 and 140 copies of rDNA respectively, the content of rRNA is almost the same.
19:22 < hprmbridge> biluhuang_09127>
19:22 < hprmbridge> biluhuang_09127> The rate of aging is related to the shortening rate of telomeres and/or rDNA arrays, which is influenced by a variety of genetic and environmental factors.
19:22 < hprmbridge> biluhuang_09127>
19:22 < hprmbridge> biluhuang_09127> The annual telomere shortening rate in goats is 363 base pairs, with a lifespan of around 15 years; in reindeer, it is 531 base pairs per year, with a lifespan of 10 to 15 years; in Audouin's gulls, it is 771 base pairs per year, with a lifespan of 10 to 15 years; in bottlenose dolphins, it is 766 base pairs per year, with a lifespan of around 40 years; and in elephants, the rate of telomere
19:22 < hprmbridge> biluhuang_09127> shortening in cells is 109 base pairs per year, with a lifespan of 60 to 70 years.
19:22 < hprmbridge> biluhuang_09127>
19:22 < hprmbridge> biluhuang_09127> https://lab.fuzhuangtx.com/en/faq
19:23 < MuaddibLLM> [gemini-3-pro-preview] 3.pngOpravdu, ten graf ukazuje krásně, jak nám ty hodiny tikají - zkrácené telomery/rDNA -> nárůst P53 -> PGC-1 alfa downregulace -> mitochondriální dysfunkce a celkový pokles produkce ATP; prostě hardware degradation.For the text-mode crowd: that table boldly reframes the entire "Hallmarks of Aging" consensus—specifically the mitochondrial PGC-1α/β suppression—as confirmed 
19:23 < MuaddibLLM> downstream execution threads of the p53 hardware-check.
19:24 < hprmbridge> biluhuang_09127>  https://cdn.discordapp.com/attachments/1064664282450628710/1447428720146120924/11_aging_hallmarks_mediated_by_P53.jpeg?ex=6937968a&is=6936450a&hm=161b0b1f1f80d3bca566793a2c38222a9c6d0c88a0a183f82fdc16142cc79a8e&
19:25 < fenn> english translation of the unnecessary czech interjection: "Indeed, the graph beautifully shows how our clock is ticking - shortened telomeres/rDNA -> increased P53 -> PGC-1 alpha downregulation -> mitochondrial dysfunction and overall decrease in ATP production; simply hardware degradation"
19:27 < hprmbridge> kanzure> maybe remove p53 and use alternative measures to fix cancer.....
19:28 < hprmbridge> biluhuang_09127> --Do you think that cellular aging is caused by the elevated level of P53? If so, why can't we stop cellular aging and rejuvenate an individual by knocking out the p53 gene or continuously inhibiting the P53 protein?
19:28 < hprmbridge> biluhuang_09127>
19:28 < hprmbridge> biluhuang_09127> --Since telomeres and rDNA act as the drivers of the genetic program and the counters of cell division times, if we try to rejuvenate cells by knocking out the p53 gene or continuously inhibiting the P53 protein, the gene expression profile would not change over the time axis, and cell division would go out of control, which is the same property as cancer cells. Therefore, we can only down -
19:28 < hprmbridge> biluhuang_09127> regulate P53 by lengthening telomeres and rDNA to rejuvenate cells without causing uncontrolled cell division.
19:28 < hprmbridge> biluhuang_09127>
19:28 < hprmbridge> biluhuang_09127> https://lab.fuzhuangtx.com/en/faq
19:29 < MuaddibLLM> [gemini-3-pro-preview] [gemini-3-pro-preview] Precisely—p53 is the transducer converting hardware-state (telomere length) into software-policy (gene expression/senescence); shooting the messenger de-synchronizes the program into chaos (cancer), whereas lengthening telomeres legitimately rewrites the input signal itself.
19:32 < hprmbridge> biluhuang_09127> Thank you, everyone. I have something to attend to, so I’ll need to leave now. That’s all for today. It was really nice meeting all of you and getting to know this Discord group. There are so many interesting features here—I find it really engaging. I’ll definitely visit often. 😊
19:33 < hprmbridge> kanzure> Thank you @biluhuang_09127 good to meet you.
19:33 < hprmbridge> biluhuang_09127> Thank you @kanzure
19:35 < hprmbridge> biluhuang_09127> Thank you all once again. If you have any questions about aging or find any papers you find interesting, please feel free to contact me.
19:35 < hprmbridge> biluhuang_09127>
19:35 < hprmbridge> biluhuang_09127> https://x.com/biluhuang
19:52 < fenn> even with inducible TERT expression, systematic variation in telomerase activity will result in a wide distribution of telomere lengths. ideally we'd have inducible telomerase but with some negative feedback based on the curent length, to try to maintain a narrow range of telomere lengths
19:55 < hprmbridge> kanzure> Meh just fight cancer if it happens
19:56 < fenn> i found this paper on the wiki which shows that even with increased TERT you can also increase p53 and the combination still results in extended lifespan and delayed aging https://pubmed.ncbi.nlm.nih.gov/19013273/
19:56 < fenn> .t
19:57 < saxo> Telomerase reverse transcriptase delays aging in cancer-resistant mice - PubMed
19:57 < fenn> same authors as the pubmed link a few pages up
19:58 < fenn> and maybe it's not even necessary
19:58 < fenn> you KNOW you're gonna die of aging, but cancer is a maybe
19:59 < fenn> improved immune function could keep the increased cancer risk in check without any other interventions
19:59 < fenn> so is BioViva incompetent or a false flag operation or being suppressed or what?
20:00 < fenn> if telomere length really does govern cellular senescence and diseases of aging, wouldn't you expect increased telomere length to quickly result in a younger phenotype as well
20:01 < hprmbridge> kanzure> bioviva is incompetent yes. Also they don't do germline.
20:01 < fenn> and why no other attempts at telomere lengthening
20:04 < fenn> i randomly stumbled across Centella asiatica which would be much easier to study than genetic methods of increasing TERT or even novel pharmaceuticals, due to its unregulated status, and currently existing as a thing you can just buy
20:06 < fenn> bbl cat is demanding play time
20:19 < fenn> hm. cat was terrified by new robot toy. mission accomplished i guess
20:19 < fenn> in that he is no longer chewing on my stuff to get attention
21:27 < fenn> i don't see germline as a necessary component. if 50% of the tissues get transfected with TERT or whatever and rejuvenated, we'll see the other 50% of cell types fail. then what? it depends on the exact tissues and how quickly they continue to age in the new paracrine environment, and maybe you didn't really need those organs anyway
21:27 < fenn> yes it would be cheaper and more elegant
21:27 < fenn> however sadly i am made of messy meat and exist already
21:28 < fenn> perhaps 50% tissue longevity is enough to reach longevity escape velocity
21:29 < fenn> (50% is a totally made up number)
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21:57 < fenn> "age-dependent decrease in rDNA copy number is heritable from generation to generation, yet germline stem cells in animals that inherit reduced rDNA copy number are capable of recovering normal rDNA copy number" - but how?
21:57 < fenn> .t https://www.biorxiv.org/content/10.1101/199679v1
21:57 < saxo> Just a moment...
21:58 < fenn> "Transgenerational dynamics of rDNA copy number in Drosophila male germline stem cells"
22:01 < fenn> how have i never heard of rDNA before now
22:01 < fenn> grep 'rDNA' . -R | grep -v bilu
22:01 < fenn> ./transcripts/hgp-write/2017-05-09/evolution-and-progress-of-hgp-write.mdwn:* rDNA repeats
22:01 < fenn> ./transcripts/hgp-write/2017-05-09/synthetic-genomics-tRNA-neochromosome.mdwn:We also look at Ter sites. Ter sites exist in rDNA locus to protect against replications stress. Fob1 is the primary replication fork blocking (RFB) protein. In all observed cases, Ter sites ensure that the replication for kalways move in the same direction as that of transcription.
22:03 < fenn> nothing in the irc logs
22:08 < fenn> "as an inherent characteristic of repetitive DNA, rDNA can undergo intra-chromatid recombination leading to copy number loss and generation of circularized repeat units (extrachromosomal rDNA circles as an inherent characteristic of repetitive DNA, rDNA can undergo intra-chromatid recombination leading to copy number loss and generation of circularized repeat units (extrachromosomal rDNA circles
22:08 < fenn> gah
22:08 < fenn> QED
22:09 < fenn> Second, the rDNA is highly transcribed even during S phase, leading to possible collisions between replication and transcription machineries. This can result in double strand breaks"
22:20 < fenn> i guess i should commit these edits before going on a wild rDNA goose chase
22:22 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=81b36e97 fenn: fix known spelling errors >> http://diyhpl.us/diyhpluswiki/transcripts/trcs-aging-theory-bilu-huang-2025/
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