P-16 protein Scandal - decades of anti-aging research

#1

This is insane. You can throw most senescent cell research and supplements such as fisetin into the garbage. Glad I never fell for the hype.

The Anti-Aging Supplement Everyone Took Never Worked

I. Executive Summary

The longevity and anti-aging scientific landscape is currently facing a profound replication crisis rooted in systemic reagent cross-reactivity and nomenclature failures. An independent methodological audit conducted by scientific whistleblower Sholto David revealed that over a decade of peer-reviewed literature investigating cellular senescence relies on fundamentally compromised observational data. Specifically, out of 334 surveyed longevity papers published in elite journals such as Nature, Nature Medicine, and Cancer Cell, 312 inadvertently utilized commercial antibodies that target the wrong protein. Due to automated search indexing optimization in major reagent catalogs, investigators seeking antibodies for the established senescence biomarker p16-INK4a (encoded by the CDKN2A gene) inadvertently purchased and deployed antibodies specific to p16-ARC (encoded by the ARPC5 gene). The latter is an abundant actin-cytoskeleton scaffolding protein with absolutely no mechanistic functional role in cell-cycle arrest, aging, or tumor suppression. Consequently, a massive body of literature asserting the correlation between “zombie” cell accumulation and distinct disease states was mapping structural scaffolding rather than true cellular aging.

While this reagent failure does not invalidate the foundational biology of senescence—which was previously confirmed via antibody-independent transgenic mouse models utilizing promoter-driven genetic suicide loops—it severely undermines the observational framework upon which the commercial senolytic supplement industry was established. Small-molecule translation has completely decoupled from rigorous experimental validation. Preclinical enthusiasm for the plant-derived flavonoid fisetin, sparked by unblinded, single-site rodent evaluations in 2018, has been definitively dismantled by high-fidelity testing. The National Institute on Aging’s Interventions Testing Program (ITP), utilizing a multi-site, blinded framework in genetically diverse mouse cohorts, demonstrated that oral fisetin exerts zero statistically significant benefit on median survival or lifespan extension. Furthermore, direct quantitative PCR transcript analysis confirmed that fisetin fails to downregulate true tissue Cdkn2a mRNA expression. This bench-level failure mirrors recent clinical data: the premier randomized, double-blind, placebo-controlled human trial of oral intermittent fisetin in patients with knee osteoarthritis showed zero therapeutic efficacy. Across all primary endpoints, including patient-reported pain indices, physical performance parameters, and direct MRI-mapped joint cartilage integrity, fisetin failed to outperform a placebo. Commercial supplement marketing has fundamentally outpaced clinical truth.

II. Insight Bullets

  • Nomenclature Confounding: Researchers systematically muddled p16-INK4a (the critical cyclin-dependent kinase inhibitor driving senescence) with p16-ARC (an actin-related protein 2/3 complex subunit 5 involved strictly in cytoskeleton architecture), as detailed by David, 2026.
  • Catalog Algorithm Failures: Automated indexing in dominant commercial antibody catalogs (e.g., Abcam, Santa Cruz) placed the irrelevant p16-ARC antibody (product code ab51243) as the premier search result for the query term “p16”.
  • Widespread Reagent Misordering: Due to a critical lack of basic sequence verification and datasheet validation, hundreds of high-profile laboratories purchased and deployed the incorrect scaffolding reagent for over a decade.
  • Scale of Literature Pollution: Out of 334 peer-reviewed longevity and aging papers audited, 312 papers (93.4%) were discovered to have utilized the wrong antibody, invalidating their main observational metrics.
  • Peer-Review Blind Spots: Systemic editorial and reviewer oversight permitted this foundational methodological error to propagate unchecked through high-impact journals including Nature, Nature Medicine, and Cancer Cell.
  • Cognitive Bias and Data Fitting: The fact that multiple papers using the incorrect antibody successfully reported expected variations in “p16” signaling highlights a widespread tendency for investigators to construct matching narratives around highly flawed data.
  • Foundational Resiliency: The underlying biological concept of cellular senescence remains scientifically sound, as the classic replicative ceiling (“Hayflick Limit”) established by Leonard Hayflick in 1961 does not rely on modern antibody affinity assays.
  • The Carrel Chicken Heart Hoax: Alexis Carrel’s historic 30-year “immortal” chicken heart culture—which long misled scientists into believing normal cells divide indefinitely—remains an anomalous artifact driven by unrecognized nutrient culture contamination.
  • SASP Pathogenicity Validated: Judith Campisi’s characterization of the Senescence-Associated Secretory Phenotype (SASP) remains verified; senescent cells actively secrete a destructive cocktail of pro-inflammatory cytokines that degrade contiguous tissues.
  • The “Zombie” Metabolic Profile: True senescent cells do not undergo quiescent apoptosis; they remain highly metabolically active, causing chronic localized tissue irritation and accelerating aging phenotypes.
  • Antibody-Independent Validation: Jan Van Deursen’s historic transgenic mouse models (INK-ATTAC) circumvented antibody errors by engineering a promoter-specific genetic suicide loop driven directly by the Cdkn2alocus.
  • Definitive Proof-of-Concept: Bypassing antibody staining entirely, genetic ablation models conclusively proved that removing true senescent cells expands healthspan and extends median lifespan in animal models.
  • The Senolytic Catalyst: The coinages of the term “senolytics” by James Kirkland in 2015 triggered massive, premature commercial capitalization on unvalidated small-molecule plant flavonoids.
  • Fisetin Preclinical Hype: Early single-site rodent data published in 2018 demonstrated outstanding senescent cell clearance, which launched thousands of consumer supplement brands before multi-site validation occurred.
  • The ITP Gold Standard: The National Institute on Aging’s Interventions Testing Program (ITP) provides unyielding validation by conducting parallel, blinded longevity experiments across three independent testing sites using genetically diverse UM-HET3 mice.
  • Fisetin Lifespan Disproof: Subjected to the strict rigor of the ITP, oral fisetin demonstrated absolutely zero statistically significant lifespan or survival benefit in either male or female mouse cohorts, as reported by Fight Aging, 2023.
  • qPCR Mechanistic Deconstruction: Bypassing corrupted antibody assays, the ITP deployed quantitative PCR (qPCR) to track tissue Cdkn2a mRNA directly; the data confirmed oral fisetin failed to reduce senescence markers in the liver, kidney, or brain.
  • Deceptive Pilot Studies: Early human single-arm pilot studies for consumer flavonoids only monitored baseline toxicity/safety and lacked control arms, which marketing teams weaponized as proof of functional efficacy.
  • Knee Osteoarthritis RCT Deficit: The first rigorous Phase I/II randomized, double-blind, placebo-controlled human trial assessing intermittent oral fisetin dosing in 74 individuals with knee osteoarthritis yielded completely negative results.
  • Objective Joint Outcomes Failure: Fisetin failed to demonstrate any clinical or statistical superiority over placebo across patient-reported pain indices, physical performance measures, or structural joint cartilage preservation quantified via objective MRI T2 relaxation mapping, as published by the Orthopaedic Research Society, 2025.
  • Pharmacokinetic Bioavailability Barriers: Pure unformulated oral flavonoids like fisetin possess extreme hydrophobic constraints and undergo rapid, aggressive systemic clearance, preventing active parent compounds from sustaining therapeutic thresholds in targeted tissues.
  • Primacy of Non-Pharmacological Interventions: Rigorous clinical data indicates that regular physical exercise successfully modulates upstream cellular senescence markers natively, bypassing the translational gaps and safety blind spots that plague current small-molecule supplements.
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Grok comparison of Fisetin and D+Q
Senolytic Therapy: What are you doing?
#2

Always knew fisetin was worthless despite how much people hyped up the mEcHaNiSmS. Well, turns out the mechanism wasn’t there either.

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#3

The genetic test seems solid for p16INK detection, but the antibody one is suspect to say the least. Hilarious that some of these papers out here that use the antibody test have published positive results.

#4
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#5

Look deeply into my eyes. Let all your tension float away. Your eyelids are getting heavy.

#6

How difficult is it going to be to go back to all of those studies and redo them to correct this mistake?

#7

I’ve followed your extensive comments on this site and have great respect for your knowledge and attention to detail.

Which is why I was surprised by your broad statement, “never fell for the hype.”

While this situation (bogus senolytics research) is absolutely unfortunate and creates mass confusion in sorting out the years of research already existing, declaring the entire senolytics field as “hype” was a bit of an overstatement and too broad of a brush not supported by the reality of the situation.

For example, James Kirkland did some outstanding research in conjunction with the Mayo Clinic years ago and has quite a bit of follow-up research. The results are strong enough to not be ignored. None of it falls in the “hype” category, nor is it contaminated by this scandal (to the best of my knowledge).

I also listened to Matt Kaeberlein dissect this situation, and his conclusion is nowhere close to your dismissive statement.

In some ways, I’m actually glad to see this news break because it will hopefully clean out a lot of bogus false positives, as well as false negatives, that have plagued recent years of senolytics research. The bad research has only created confusion and obfuscated our ability to parse signal from noise.

Adding to the confusion, people collapse “senolytics” research conclusions into one bucket comparing fisetin-alone results to D+Q (and various other isolated treatment protocols), which are night-and-day different and must be parsed to draw reasonable conclusions.

Yes, this controversy is a bummer in some ways, creating mass confusion in my mind from all the historical research in my head. What remains true? What should be discounted? It’s an unfortunate mess to have to sort out.

However, the optimist in me believes future senolytics research (of which, there is a lot in the pipeline) will benefit. The standards should tighten because of this documented failure. That’s a good thing.

My point is how this situation is far from the damning conclusion you presented in your headline to this thread. The numbers of actual violators and the papers indicated do not align with your conclusion that the entire field of senolytics was “hype.”

I’m not trying to take you to task here because, again, I’ve gotten great value from your extensive posts on this forum and respect your views. I just think you missed the mark with this one, and I think the topic of senolytics is important enough to justify a more balanced analysis of what actually happened here and what remains standing after the dust is settled. There’s no value in leading this thread into a negative group-think spiral, which the follow-on comments align with.

I remain confident that there is a there there with senolytics. The conflicting, low-quality research in the recent past has clouded the picture. Hopefully, this becomes a positive step toward cleaning up the mess and points us in a positive direction.

I welcome any quality research that leads me to a longer, healthier life - including senolytics.

Hope that helps!

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#8

Using free Claude Haiku 4.5, I asked whether fisetin might still be a legitimate senolytic if P-16 is disregarded. Other bigger and badder AIs may differ, but here’s what I got:

Based on the primary fisetin studies, fisetin would still demonstrate meaningful senolytic activity even excluding all p16INK4a data, because the research documented senescent cell elimination using multiple independent markers. Here’s what remains:

Evidence Independent of p16INK4a

Animal Studies (Naturally Aged Mice)

The landmark study, Yousefzadeh et al. (2018), explicitly stated they were measuring senescence markers beyond p16 because “not all senescent cells are p16INK4a positive: some are p21CIP1 positive, but p16INK4a negative.” Their non-p16 findings in naturally aged mice include:

Marker Finding in Aged Mice Result After Fisetin Treatment
SA-β-gal activity Significantly elevated in white adipose tissue Significantly reduced in tissue sections
p21Cip1 mRNA Elevated in fat, spleen, liver, kidney Significantly reduced in all tissues
SASP cytokines (IL-1β, IL-6, TNF-α, IL-10, MCP-1, PAI-1) Markedly elevated in aged mice Significantly reduced across tissues
Oxidative stress (4-HNE adducts, glutathione ratio) Elevated Improved—GSH/GSSG ratio increased, lipid peroxidation decreased
Circulating MCP-1 Elevated in aged mice blood Reduced
CD3+ T cell markers p21 and SASP elevated Reduced

Functional Outcomes in Aged Mice

Fisetin-treated mice showed measurable improvements independent of any p16 data:

  • Extended lifespan (statistically significant in late-life intervention at 85+ weeks of age)
  • Improved physical function (they measured composite lesion scores showing reduced age-related pathologies in multiple tissues)
  • Reduced organ dysfunction markers in liver and pancreas (ALT and amylase levels improved)

The Critical Weakness

The one major vulnerability is the CyTOF cell population analysis, which used p16-luciferase transgenic mice and specifically identified which cell types (mesenchymal stem cells, T lymphocytes, NK cells, endothelial cells) had senescent cells reduced. That data cannot be salvaged if p16 measurements are unreliable.

However, the SA-β-gal staining in naturally aged wild-type mice (non-transgenic) showed fisetin reduced senescent cells overall in white adipose tissue, which provides independent confirmation that senescent cells (however defined) were eliminated.

Human Studies

Clinical evidence is minimally affected by p16INK4a concerns, since the limited human trials with senolytics (dasatinib + quercetin) measured:

  • SA-β-gal+ cells in adipose tissue: 62% reduction 11 days after treatment
  • p21CIP1+ cells: Significantly reduced
  • SASP factors in blood (IL-6, IL-1α, MMPs): All reduced

These weren’t p16-dependent measurements.

Bottom Line

Yes, fisetin would still be a credible senolytic without p16 data, because:

  1. p21Cip1 reductions are independent evidence that cells with CDK inhibitor expression were reduced
  2. SA-β-gal reduction is the classical senescence marker and doesn’t depend on p16
  3. SASP reductions are a hallmark outcome—inflammatory cytokine levels dropped consistently across tissues
  4. Lifespan extension and functional improvements are hard to explain without actual senescent cell reduction
  5. Oxidative stress improvement suggests mitochondrial/metabolic recovery consistent with senescent cell clearance

The claims would be somewhat weaker than currently stated (you’d lose the detailed cell-type breakdown from CyTOF), but the fundamental evidence for efficacy would remain intact from p21, SA-β-gal, SASP, and functional measures.

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#9

A small misunderstanding - when I said “hype” I was referring to fisetin specifically. That said, I am not super enthused about the whole senolytics field either, at least in its current incarnation. There was a lot of hope (and hype!) when the whole field was hot, but the first implementations (knee joint) were largely a failure. Subsequently, it was understood that wholesale elimination of senescent cells was not beneficial in the first place, and the agents available were a bit of a blunt instrument lacking specificity anyhow.

I am not saying there is no value to the field or the concept itself. But my suspicion is that senomorphics is a more fruitful approach. The idea is not to simply eliminate senescent cells - that strikes me as a dead end. You can keep eliminating cells in order to avoid SASP, but what is the end game - down to zero cells of any kind left? I think the goal ought to be to avoid the need for cells to turn senescent in the first place - that way you entirely avoid the question of elimination to get rid of SASP. I mean - you want to avoid or slow down the aging process itself, not just hack away at the consequences. That’s the Holy Grail. I’d rather not age instead of getting rid of liver spots as they spring up. The goal is for them not to spring up in the first place.

It seems to me, that senolytics is just a tributary in the whole river leading to the ocean of real impactful anti-aging interventions. Going up the tributary itself will not lead to the promised land, IMHO.

The senolytics research I have seen to date doesn’t bowl me over, but perhaps I’m missing something - entirely possible. I am happy to be proven wrong - I’ll go to wherever the evidence leads me to, after all, the goal is not to have one’s pet theories proven right, but finding the truth. If I’m wrong about the field, I’m all ears.

So I wouldn’t say there is no value in the field of senolytics, but in immediate practical terms, as in currently available agents I personally find none compelling and some I think are just hype (like fisetin - which I never took regardless of any hype). That said, as always - if someone finds some molecule helpful in their personal health situation, well, nobody can quarrel with that and more power to them. YMMV.

#10

I think there is a lot of confusion about senescence. A lot of the in vitro testing is of human cells that have been stressed into senescence in a way in which they would not be stressed in vivo. I don’t see much value in the results of those tests.

As people know I think we need to look at what functionally senescent cells are. I think they are mainly cells that were intended to become somatic cells, but have failed to make that step. I think that is linked to a mixture of SLC25A1 expression and mitochondrial efficiency.

In Osteoporosis the osteoblasts fail to differentiate properly. I think they go senescent.

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#11

True enough. A lot of this research is very low value. Cells become senescent for distinct reasons, be it as an anti-cancer strategy or because they failed in some way. Merely eliminating them seems like a very simplistic approach. Everything starts upstream, long before the senescence processes initiate. That’s where the gold lies, seems to me.

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#12

I think it is an anti-cancer strategy, but I agree with Thomas Seyfried on cancer.

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#13

The real problem is that p16INK4a has become such an established senescence marker that if your western blots don’t show it, reviewers automatically assume your paper has no value, and your paper gets blocked. I’ve seen plenty of researchers buy the wrong antibody, fail to get a band, and end up having to settle for low-impact journals.

Worse, some straight-up falsified their data. They used p16-ARC to fake a p16INK4a band. You could give them the benefit of the doubt and claim it was just a copy-paste error with the antibody names, but how do you explain the massive wave of papers showing p16 bands in p16-deficient cell lines? That’s not carelessness; it’s deliberate fraud just to cater to reviewer bias.

Science has to withstand scrutiny. That’s exactly why I never look down on low-impact journals—there’s still a ton of gold buried in them. @adssx @CronosTempi

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#14

CANCER THERAPY - that induces cancer cells into senescence and then kills the senescent cells

This is an emerging area of cancer research.

CANCER THERAPY - that induces cancer cells into se.pdf (554.3 KB)

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#15

@Todd thank you for being the voice of reason and discernment

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#16

Stanfield’s framing “it never worked, it’s over” is overstated. The honest assessment is:

  • Lifespan extension in genetically diverse mice: failed (Harrison DE et al., GeroScience, December 2023.)
  • Senolytic effect in specific mouse frailty models: promising, recent (Murray et al., Aging Cell, May 28, 2025)
  • Human anti-aging efficacy: genuinely unknown as most trials are still running
  • Human efficacy in specific disease contexts (stroke, cancer inflammation): some positive signal (Wang et al., Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial. 2019)

I couldn’t get through your entire post because you started it with a pretty loaded sensationalist statement. The foundational biology isn’t debunked at all. Stanfield says “Van Deursen’s kill switch was genetic — it targeted the cells through the gene itself and a drug trigger. There was no antibody involved. So the strongest evidence that clearing senescent cells actually helps an animal does not depend, even a little, on the broken antibody David found. That’s why careful aging scientists — Matt Kaeberlein among them — have been saying the antibody mistake doesn’t debunk the underlying biology. And on that, they’re right. The proof that zombie cells matter comes from these genetic experiments and other lines of evidence, not from the molecule that got mislabelled”

What’s shaky is the huge pile of correlational papers built on top of it using the flawed antibody, which made the whole field look more “settled” than it was. I think senolytics will be a huge field by 2040 and targeted senolytic therapies will make a significant impact on lifespan and overall aging. SenoVax is a great example of a targeted therapy using your own immune system to target senescent cells. The treatment is coupled with StemCellRevivify which aims to replace the cells that have been lost to senescence.

As for Fisetin, I take Bio-Fisetin for improved bioavailability and will continue to take it. It may not affect senescence, although I’m not entirely sold on that yet, but it most likely does have other positive effects. Current initial evidence shows that Fisetin has positive effects on the vascular system, muscle and frailty, and neuroprotection. Further human studies will be required to confirm this. However, to say that senescence isn’t a valid target of research is very inappropriate.

Sources:

  • Mahoney et al., Aging Cell, March 2024 (DOI: 10.1111/acel.14060) found that intermittent oral fisetin supplementation in old mice reduced vascular cell senescence and SASP inflammatory factors in the vasculature, improved endothelial function by increasing nitric oxide bioavailability, and reduced aortic stiffness — with ROS levels in arteries lowered by 2.6-fold.
  • Mahoney et al., Aging Cell, April 2026 (DOI: 10.1111/acel.70500) used single-cell transcriptomics to identify that fisetin improves endothelial function by targeting senescent endothelial cell-derived SASP factors, specifically identifying CXCL12 as a key mediator. They showed SA-β-gal positive senescent cells were 86% lower in arteries exposed to plasma from old fisetin-treated mice versus old vehicle mice.
  • Murray et al., Aging Cell, May 2025 (DOI: 10.1111/acel.70114) found that fisetin attenuated age-related declines in frailty and grip strength in old mice, that these improvements were accompanied by lower expression of senescence-related genes in skeletal muscle, and that the degree of improvement was not statistically different from genetic clearance of p16+ senescent cells — the gold standard experimental approach.
  • Currais et al., J. Gerontology, 2018 (PMID: 28575152) found in SAMP8 rapidly-aging mice (a model for sporadic Alzheimer’s) that fisetin reduced cognitive deficits in old mice while restoring multiple markers of synaptic function, stress signaling, and inflammation, using an integrative approach correlating brain protein expression and metabolite levels with cognition. Earlier work showed similar results in transgenic Alzheimer’s mice. No human cognitive trial results exist yet.

Things to keep an eye on:

  • Three COVID-related Phase 2 placebo-controlled trials of fisetin were sponsored by Mayo Clinic / NIA through the Translational Geroscience Network: COVID-FIS (nursing home residents, NCT04537299), COVFIS-HOME (at-risk outpatients, NCT04771611), and COVID-FISETIN (hospitalized adults, NCT04476953). These were multi-site trials involving Harvard, Johns Hopkins, Wake Forest, and several major universities. The nursing home trial completed in late 2024 and posted results August 2025, but the full published paper isn’t yet available. The hospitalized adults trial is still active with primary completion expected September 2026.
  • The TROFFi trial (Phase II double-blind RCT in frail breast cancer survivors, NCT05595499, testing 20mg/kg fisetin on physical function, senescence biomarkers, and quality of life) is also ongoing.
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#17

Before LLMs were usable I identified Fisetin as a HDAC/KDAC inhibitor. It is a little more complex than that and I will copy below a result from chatGPT(5.5paid).

I tend to look at things through an acetylation pathway lens. I have fisetin as one of a long list of HDACi/KDACi s that I use when going a bit into deacetylatse inhibition. That, however, is an odd tool as it varies from class to class and I much prefer increasing acetylation. Hence I tend not that much now to go for all of the inihbitors.

I think that is the key benefit if any of fisetin.

chatGPT(5.5paid)

The clearest answer is: I found papers saying fisetin inhibits HDAC activity, but I did not find a primary paper giving a true experimentally measured HDAC IC50 for fisetin. The figures often quoted are either % inhibition at fixed concentrations, cell-viability IC50, or docking-derived Ki, not enzyme IC50.

Paper What it showed HDAC IC50?
Kumboonma et al., “Histone Deacetylase Inhibitors and Antioxidants From the Root of Gluta usitata”, Natural Product Communications, 2019 Isolated fisetin and tested it in a Fluor-de-Lys HDAC activity assay using HeLa nuclear extract. Fisetin inhibited HDAC activity 18.2 ± 0.7% at 1 µM and 88.3 ± 0.8% at 100 µM. TSA at 25 µM gave 96.1 ± 1.4% inhibition. (Sage Journals) No experimental IC50 reported.
Same paper: molecular docking Docking-predicted inhibition constants for fisetin: HDAC8 Ki 1.20 µM, HDAC2 Ki 11.02 µM, HDAC7 Ki 30.80 µM, HDAC4 Ki 61.87 µM. These are in silico Ki values, not measured IC50s. (Sage Journals) Not IC50; docking Ki only.
Afroze et al., “Fisetin Suppresses the Proliferative and Migratory Behavior of HeLa Cells by Modulating Aberrant Epigenetic Marks (Writers and Erasers)”, Epigenomes, 2026 Cell-based study: fisetin 20–50 µM dose-dependently inhibited DNMT, HDAC, HAT and HMT activities after 48 h, with 24–72% inhibition vs control. It also reduced expression of several HDACs including HDAC2, HDAC4, HDAC7 and HDAC10. (PMC) No HDAC IC50 found.
Afroze et al., “Fisetin Deters Cell Proliferation, Induces Apoptosis…” 2022 Mainly a HeLa cytotoxicity/apoptosis paper. It reports fisetin cell viability IC50 = 50 µM at 48 h, not HDAC enzyme IC50. (ResearchGate) Not HDAC IC50.

So, if you need a single practical number, the best experimentally grounded statement is:

Fisetin inhibited mixed HDAC activity from HeLa nuclear extract by ~88% at 100 µM and ~18% at 1 µM; no direct enzyme IC50 was reported. (Sage Journals)

A rough interpolation from those two points would put the apparent mixed-HDAC IC50 somewhere in the low tens of µM, but that would be an estimate, not a reported value. The oft-seen 1.20 µM value is docking-predicted Ki for HDAC8, not an experimental IC50.

#18

It seems to me that we can barely define a senescent cell. So imagining that we can somehow selectively inhibit or kill them is claiming something miraculous. I mean, can we do that with anything else? Nope.

#19

That’s the key - a tremendous variety of ways cells age - we can arbitrarily pick a set of variables/biomarkers that when met we now define as “senescent”. But that’s a bit of a word game as to when there are enough changes to now suddenly say a cell has reached senescence.

Anyhow, there are subsets of senescence, where a cell stops dividing as a defensive measure against cancer, but even here it’s often not specifically “pushed” to senescence by a cancer process (like p-53), but a global setting for cells that evolved as a general measure against uncontrolled proliferation - sort of like “insurance”, it’s there not necessarily because you will have a cancer event, but you might.

That is why dealing with senescent cells through elimination by senolytics or ameliorating the consequences of SASP, while interesting as far as it goes, is less interesting to me than pursuing anti-aging further upstream, before age related changes occur.

Here is an example - if you can eliminate the possibility of cancer development, you eliminate that reason for cell senescence, and don’t have to deal with subsequent consequences or senolytic rescue. That’s upstream of the issue. Is it realistic? Not only is it realistic, it actually already happens - widely. Naked mole rats virtually never get cancer… and don’t appear to senesce/age in conventional ways at all. Same for shark species, molluscs and the like - no cancer, and no classical “aging”. How do they do it is remarkably diverse - there is a variety of ways, including mechanisms assuring great DNA/Rna encoding fidelity, and cell membrane integrity and so on (read up on NMR cancer resilience - fascinating) - so mammals do it, fish do it, birds do it etc.

If we can implement genetic coding in humans of such solutions, you would eliminate cancer and take a giant step in anti-aging. The map is already out there - study those animal designs, adjust and implement. That is far more impactful than any senolytic. That’s the future of anti-aging - senolytics by contrast is a dead end. Yes, there are likely ways senolytics can deal with the consequences of cell aging, but prevention is where it’s at.

#20

Hello Todd,
I find also important to note that many (especially interventional) studies did not rely solely on Western blot or IHC with the misidentified p16 antibodies. They often used orthogonal methods like qPCR, genetic reporters, SA-β-gal, SASP panels, and functional outcomes.

So, it seems to me that we need to separate the wheat from the chaff, which is a constant necessity in science.

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