Young Cell Therapy, The Ship of Theseus, Facts and Fiction There is a lot of buzz concerning a recent report that young tissues when transplanted into old animals are inappropriately aged as a result. Some people therefore conclude that there is no point in transplanting young cells and tissues into old people. If the concept is we can keep people going by replacing dysfunctional cells with young ones the way an antique car can keep going by replacing old parts with new ones (Ship of Theseus scenario), the objection would be “that won’t work because the new spark plug becomes old the minute you install it in the old car.” I don’t dispute the data in this paper (referenced in the link below, though I do have one concern also discussed below) but I do strongly object to the conclusion that this phenomenon is demonstrated to be of consequence. Here are some facts not addressed in the paper: Age reversal such as when old cells are reprogrammed by OSLN, or OSKM, often does not reset the methylation status of the adult cells. It can, however, reset developmental aging, the telomere clock etc. Despite retaining important sites of adult methylation, the cells can be turned into young mice. So, in that case where aging is reversed, how important are some of these methylation markers? There is no reason to believe, indeed it would seem unlikely, that transplanting a young heart into an old counterpart would significantly affect telomere length. So, that important marker of aging would likely not be inappropriately aged. The strategy for making young replacement cells for old people commonly centers on pluripotent stem cell-derived cells. There the problem most scientists face is the converse (ie the cells do not easily take on an adult-like age). In many respects that is beneficial as the cells are in an early regenerative state (but the opposite problem discussed in the paper). Lastly, even if the engraftment of say a young heart into an old human accelerated the aging of the donor heart, in many cases a heart with some aged markers would be preferable to the expected outcome of heart failure, for example. I would also point out that there are other potential explanations for the shift in methylation discussed in the paper in the young heart engrafted in an old animal If, for instance, the surgery itself and wound repair was impaired in the old animals, an inflammatory response could trigger methylation changes. Oddly, in the paper the methylation clocks that could show if this was the case DO NOT show the sham surgery controls (Figs 1c,d, and e). The sham surgeries would address that interpretation. The sham controls are shown only in the data of the other methylation clocks where no difference was detected (Figs 1f-n). I would appreciate it if the lab explained why that data was omitted. It is critical if one is to interpret the significance of the data in the paper. @Nature @antonioregalado @aubreydegrey @jpsenescence @pknoepfler x.com/nature/status/21044930…

The Overton Window and Human Therapeutic Cloning   Our project to isolate human embryonic stem (hES) cells in the late 1990s was aimed at creating a practical means of making young cells of any type to repair tissues in people with age-related degenerative disease ( a field that came to be called “regenerative medicine”). This isolation of hES cells generated enormous controversy, largely because of the misconception that the cells were derived from pregnancies. But our first efforts to reprogram the aging of human cells by means of cloning (somatic cell nuclear transfer) eclipsed even the hES cell controversy because, in part, many believed our real intent was to clone human beings.   A friend of mine recently provided me with a VHS recording of this Senate Hearing. For those interested in public policy, this video may have value in documenting the Overton Window in action. Of course, shortly after these hearings, we at ACT developed the use of OCT4, SOX2, NANOG, and LIN28 and Shinya Yamanaka developed OCT4, SOX2, KLF4, and MYC as a simple means of reprogramming cells and reversing developmental aging (iPS cells) without using oocytes.   Pasted below is some of the open discussion in that hearing. I must say, to this day, I was and am impressed by the sincerity and bipartisan efforts of Tom Harkin and Arlen Specter in fighting for the greatest good for the greatest number of people. youtu.be/S-r9emP9O4g?si=7xv6…

In the above post I said “knocking out the receptor for GH.” I meant to say “antagonizing the receptor for GH.” They used a mutated form of GH that no longer was an effective agonist and instead functioned as an antagonist (GHA).

Is Supplementing Growth Hormone/IGF1 Slowing, Reversing, or Accelerating Aging? Many people take human growth hormone to supposedly rewind the clock of aging. Yet many of us in molecular gerontology believe that is exactly backward! That is, many of us believe high GH or its downstream protein IGF1 shortens longevity. This is therefore a topic which REALLY needs more public awareness. Aubrey de Grey and I just started a discussion of the known scientific facts about Growth Hormone and its downstream factor IGF1 in another thread, but given its importance, I invite some of my colleagues to join here and discuss what are the best data as of today. There is a lot of background everyone should know. Perhaps a good starting point is to read the paper pasted below. It provides a nice review and a lot of data on correlations of IGF1 levels with health. It is a UK Biobank analysis of 440,185 people. They found that IGF1 associations change with age. Higher IGF1 appeared to correlate with relative protection in younger individuals, whereas the adverse association of high IGF1 became stronger with increasing age. At the same time we must acknowledge that very low IGF1 which leads to say, muscle frailty etc could potentially benefit from GH or IGF1 despite elevating other risks. I also liked that scatterplot in their paper which shows the immense variation of IGF1 levels in people with many older people having higher levels than young. It is often said IGF1 levels fall with age but it is not so impressive when you take a close look at actual data. So, please free to weigh in everyone. Is supplemental Growth Hormone of IGF1 slowing or accelerating aging? My view is that they accelerate (not slow) the overall aging process. They allow you to live fast, play hard, and leave a good-looking corpse. I’m happy to convinced otherwise… @aubreydegrey @jpsenescence @BKennedy_aging @davidasinclair pmc.ncbi.nlm.nih.gov/article…

The Explanatory Power of the Senescence Associated Secretory Phenotype (SASP) In the mid 1980s I was studying human cell senescence (the Hayflick phenomenon) as a graduate student. I asked myself how cellular aging could cause the changes we see in the aging human body. Sure, if cells ceased replicating in significant numbers, one could imagine it could play out as disease. But I felt that wasn’t the whole picture. A recent post by @jdudley on the aging effects of TIMP2 induced me to explain here some important parts of the biology of aging. When I was young, my father asked me to lay my hand down on the table next to his. He then pinched the skin on the back of his hand. His stayed up like a ridge of putty. Mine snapped back quickly. “That’s aging,” he said. As a graduate student I knew that if my dad knew cell biology he would have said, “loss of elastin, someone should figure that out.” Elastin as it’s name implies, is an elastic rubber band-like protein outside of cells (the extracellular matrix). As a PhD student I decided to do the logical experiment. I took young skin fibroblasts, grew them to senescence, then fed each a radioactive building block of protein which would allow me to see and potentially identify differences occurring with aging cells. I discovered some really obvious differences. There are some proteins that tear down the extracellular matrix called “proteases” and inhibitors like TIMP1 and 2. I discovered a cascade where plasminogen activators activate plasmin which in turn activate metalloproteinases that can destroy elastin. The question then was, so, is that really a part of the aging cascade? There was one way back then to find out. There was at the time a researcher named Victor Almon McKusick (1921–2008) at Johns Hopkins University School of Medicine. He was recognized as the "father of medical genetics.” He had led an effort to create a comprehensive catalog of human genes and genetic disorders. I wrote him and asked what if any medical conditions occur with elastin was destroyed or just not produced normally. He sent me the picture pasted below. The woman on the left is 16 and the daughter of the woman on the right. The daughter on the left had cutis laxa, an inherited disorder in elastin. I was really impressed to see cell senescence could have such powerful explanatory power in the aging human body. I used to call this property of senescent cells “senstatic activation.” Just Campisi called it SASP. Whatever term you use, it seems clear that these few pieces of the puzzle of the biology of aging were figured out decades ago. Since then many more pieces have been assembled in like manner (albeit now at a breathtaking pace). I am of the opinion that one can now see how the diverse observations like sirtuins, NAD, progeria, Werner syndrome, cell aging (telomeres), mTOR, lipofuscin, etc fit together into an understandable and unified picture puzzle of aging. More to come… @jdudley

Critique/Comments on Generation Labs Presentation “Breakthrough Science to Reverse Aging.” I previously defended a scientist associated with Generation Labs as a reputable scientist. I stand by that. However on viewing the presentation pasted below I must state as vociferously as I can how strongly I recoil in abject horror at the claims being made. All of these comments are my honest opinion, so take my opinion for what is worth. I could be misunderstanding the presentation, it looks like some parts were not filmed so perhaps data was shown we can’t see, etc… I am not suggesting impropriety of any sort, and happy to exchange points of view and retract my opinion if I am missing something. First, the opening slide “Breakthrough Science to Reverse Aging.” As you will see below, I question essentially every word. Is it really breakthrough, is it really science, and does it actually reverse aging? The foundation of the company appears to be a diagnostic of biological age based largely on blood chemistry and assays of markers of aging called SystemAge. The presenter dramatically announces with a drum roll, as though it were Steve Jobs announcing the product launch of the iPhone, a box with four syringes named “One Generation.” The claim is made that this non-disclosed therapeutic is the first ever longevity therapeutic to be proven to be working in the human body targeting aging itself. The claim seems to be made that it activate[s] regeneration and improves function in the heart, brain, blood vessels, muscle, vision, fertility… where btw is all that proven data? I believe that to any reasonable person, this description implies that the product actually reverses the aging process and induces regeneration itself not just markers associated with these processes. For example, statins lower cholesterol markers but few believe that is because they actually reverse aging in the coronaries. Does One Generation truly reverse aging? How about cellular aging throughout the body for example? I don’t see any such data. The presenter does show anecdotal data from eight individuals with one stating “I never want to stop taking this” claiming, as I understand it, an energy boost. Such claims are, IMO, not taken seriously, and are frowned upon by those in the pharma industry. The most scientific reason is simply the placebo effect. We have seen many times how people believe a new drug is dramatically improving their sense of well-being, energy, libido, etc when in reality they were assigned the sugar pill (placebo). That is why in drug development double blinded placebo-controlled trials are used where neither the patient or the physician knows whether the patient actually received the drug being tested. The presenter showed IGF1 levels being increased in individuals following treatment. IMO, that is not a good thing. One of the most universally-accepted facts about aging is that elevated IGF1 levels leads to shorted lifespans and lower IGF1 levels to longer ones. Whatever is in the syringes of Generation Lab’s product designated “One Generation,” I hope the company intends to launch FDA-approved human trials rather than the product itself. How could we possibly know if it benefits human health let alone reverses aging without controlled safety and efficacy trials and extensive histological, molecular, and pathological studies showing it targets said aging process? The presenter claims One Generation will lead to an era of ageless generation. I for one would love that to be the case. I have devoted 46 years of my life to aging research. Nevertheless, I vigorously oppose the way this product is being presented. It saddens me to share criticisms, but I feel an obligation to share my opinion that making claims of this sort without rigorous support could hurt the scientific enterprise and medicine itself. @aubreydegrey @antonioregalado @EricTopol @jpsenescence @mkaeberlein @davidasinclair youtu.be/6MR7lUb2vOY?is=hU9Z…

DNA Methylation Clocks, Aging, and Interventions DNA is the genetic blueprint of life. It is therefore only logical to ask the highly-relevant question as to whether there are regions in the DNA code that control our lifespan and aging process. I say it’s logical because we know the DNA blueprint controls the pace and steps in the development of the human body. And certain mutations in the code can lead to diseases of premature aging. Years ago we demonstrated that the linear ends of the DNA strands function as such a clock of aging. We proved that by resetting the telomere clock with the immortalizing gene telomerase. Are there other clocks and if so, do they control the rate of aging or merely reflect downstream consequences of aging? That is the debate currently underway in regard to DNA methylation clocks. DNA is composed of a string of bases commonly referred to as G, A, T, and C. The “C” base can be modified by the addition of a methyl group -CH3. This labeling of the C is thought to play a role in which genes are turned off or on. By looking at some particular sites in our DNA in say a blood sample to see if the C is methylated, one can fairly-accurately predict the age of the person from which the blood was drawn. Most people already know how old they are, so that use isn’t particularly useful. But, what if it could be used to measure the aging or incidence of age-related disease in organs throughout the body? That would be VERY useful such as in providing a simple measure of effectiveness of interventional strategies in aging. Whether a blood-based methylation clock can be developed with useful sensitivity and specificity is what the current debate is over. @mkaeberlein points out that there is still much work to be done to validate such tests. @RV_sehgal defended his recent papers largely on the grounds that the results described in the papers are accurately reported. This is exactly what is so valuable about science. It is all about finding the truth and sparring with one’s colleagues to sharpen our interpretation of data. With that in mind, I will throw in my two cents… The (Sehgal et al., Nature Aging 2025) paper demonstrates that the system scores (and Systems Age) are associated with and have discriminative ability for organ-relevant outcomes on independent data, and that this discrimination is often better than or comparable to existing global epigenetic clocks. However, it does not provide the classic sensitivity/specificity numbers that would tell you, for example, “at this threshold the test detects X% of future cases while correctly ruling out Y% of non-cases.” Those metrics do not appear to be in the paper (main text or the freely described supplements (unless I missed something)). Those are the types of results that are the sine qua non for diagnostic development. In the most recent paper Sehgal, R., Borrus, D., Armstrong, J.F. et al. Responsiveness of epigenetic aging biomarkers to longevity interventions in humans. Nature Medicine (2026) such testing data on sensitivity/specificity in a testing set are still not reported. Furthermore, it is still a nagging question as to whether these methylation marks reflect true “aging” biology (or inflammation marks or both). 
Many second-generation clocks (including parts of SystemsAge and GrimAge-family clocks) were trained, after all, on composite clinical risk factors (e.g., inflammation markers). Observed reductions may therefore reflect temporary improvements in intermediate states (inflammation, metabolism, immune cell composition) rather than a fundamental slowing of aging. Lastly, unless one is to believe that inflammation is a central cause of aging, it is hard (at least for me) to understand how epigenetic changes in blood cell DNA would correlate with age-related degenerative conditions in other tissues/organs. Of course, sciences surprises us all the time. That is what makes research such an adventure.

The Scientific Use of the Term “Immortality.” Have we learned how to make human cells immortal? Absolutely. Is there confusion about what we mean by that? That’s a yes there as well. I will clarify the terminology and the implications for interventional gerontology. The word “immortality” derives from the Latin adjective “mortalis” meaning subject to death. The prefix “Im-“ means “not” so immortalis means not subject to death or imperishable. To most people the word has a strictly religious connotation. Based on classical Greek influence, Christianity adopted the idea that the soul was immortal (deathless AND indestructible) despite the obvious mortal nature of our bodies. So why do scientists use the term? It all began with one of my favorite scientists named August Weismann in the 1800s. Weismann was a biologist and thought a lot about evolution and the fact that very early in the history of life on Earth, life was all single cells swimming around in the ocean ceaselessly replicating themselves. Weismann proposed that the origin of aging and inevitable death occurred when some of these single-cell animals changed and clumped together. They evolved in such a way that they had two paths, twin potential destinies. Some of the cells in the multicellular clump could keep the ceaseless replication going. He called those cells “germ line” cells as they could continue forever making new “clumps.” The rest of the cells in the clump evolved to support their sister germ line cells by attracting food and other means of support. He called the latter “somatic” cells (literally meaning “body” cells). Weismann suggested that since the germ line cells were doing the ceaseless replication and the somatic cells were doing the support function, the somatic cells didn’t really need the ability to replicate ceaselessly. So like cave animals that lose the ability to see when they live their lives in dark caves (because vision isn’t needed), the ability for ceaseless replication was lost in somatic cells. Weismann then used the word “immortality” for the ceaseless replication of the germ line cells, and “mortality” for the finite lifespan of the somatic cell counterparts. Weismann got a lot of pushback from the scientific community over this choice of words as we can see below: Excerpt from Nature, Vol. 38, No. 978 (July 26, 1888): "In introducing the term 'immortality' into the domain of cellular biology, Prof. Weismann has borrowed a concept that belongs properly to theology and classical mythology, rather than to natural science. To the ancient mind, and specifically in the conception of the Greek gods, immortality (athanasia) implied an absolute, inherent quality—an unassailable exemption from death, immune alike to internal decay and external destruction. The gods of Olympus could neither perish by disease nor be slain by violence; their duration was unconditioned.” Nevertheless, the choice of words stuck and is standard terminology today in cell biology. When I walked my mom through our labs at Geron in the late 1990s, we had just isolated the immortalizing gene telomerase. I showed her a dish of Len Hayflick’s skin cells that I had immortalized with the gene. She recoiled with an alarmed expression. “What are you thinking,” I asked. “You can’t kill them with ANYTHING” she asked… So, here is the nub of the confusion. When we refer to “cell immortalization” we mean that we have given somatic cells the potential replicative immortality of the germ line. They are NOT indestructible. Run over them with a truck and they are dead. The same is true for humans. The goal is to improve how we age and mankind will likely immortalize our bodies someday. However, we will almost certainly not be the indestructible Juggernaut of cartoon fame. We will still be vulnerable to accidental death (at least for the foreseeable future). youtu.be/s7l6d1BclNQ?is=TxGS…

Aging, Epigenetics, and the Reprogramming (Reversal) of Cell Aging David Sinclair posted an interesting paper on the epigenetic reprogramming of cells in the very early mouse Embryo (Paper titled: “Lempel-Ziv Complexity and Structural Features of DNA Methylation Reveal Epigenetic Rejuvenation in Mouse Embryogenesis”). I have some qualms about the paper since the authors themselves point out that their statistical significance data should be “interpreted as exploratory rather than confirmatory.” Nevertheless, David is highlighting important biology here. Clearly the epigenetics of DNA is reset back to the beginning of life in these early embryos. It is critical to understand how that works if we are to safely and effectively reprogram (reverse) developmental aging. It is commonly stated that partial reprogramming reverses aging. As I pointed out in a previous post, genes like OSKM can indeed revert cells back to these first cells in the development of our bodies (iPS cells). In iPSCs, telomerase can even rewind the cell aging clock. But in partial reprogramming of human cells, it appears that telomere length in not reset (again in humans, not clear in mice). But, even in regard to the commonly-used DNA methylation age, the methylation profile of genes associated with the repression of regeneration in the Embryonic-Fetal Transition (EFT) are often not reprogrammed even when reprogramming is complete to obtain iPSCs (see figure I pasted below of whole genome BID sequencing in ES cells, pre-EFT regenerative cells, post-EFT nonregenerative cells, iPSCs made from PreEFT cells and iPSCs made from adult post-EFT nonregenerative cells. This is, I suggest, telling us something important about the age reversal potential of genes like OSKM. The genes can effectively reprogram extremely important molecular pathways unlocking embryonic regenerative potential (the reprogramming of COX7A1 gene expression for example), but when applied transiently (partial reprogramming), the lack of resetting of the telomere cell aging clock and methylation of some genes like COX7A1, show that they do not perform uniform or complete age-reversal. @davidasinclair

Pharmacologic Intervention in Metabolic Pathways and Aging One of the oldest observations in aging research is that caloric restriction can increase health span and lifespan in numerous animal models. For this and other reasons some researchers focused on metabolism to understand and intervene in aging. More recently, the role of cellular aging (the Hayflick limit) has been emphasized based on programmatic molecular mechanisms (restriction of telomerase expression in somatic cells). A recent paper by Irina Conboy’s group (pasted below) proposes a cocktail of small molecules is capable of targeting both pathways (i.e. metabolic pathways and thereby eliminating senescent cells (senolytic therapy)) without targeting the actual clocking mechanisms like telomere shortening etc. According to a piece written by Antonio Regalado, some individuals are taking a combination drug therapy from the Conboy group and they claim increased vitality. If we are to assume that said cocktail is the one described in the article pasted below, I would posit that the correct path for drug development is to conduct extensive animal preclinical studies to assure safety and efficacy of new therapeutics followed by placebo-controlled studies as opposed to performing and allowing the circulation of anecdotal results. It is well-established that people who believe they are taking a drug that could benefit them can show almost “miraculous” reductions in symptoms for a host of disorders (placebo effects). Lastly, I would point out that in the study below, both the anti-cancer and anti-aging effects are discussed. It is important to remember that mice generally die of cancer, so decreased cancer incidence would naturally increase their longevity. All honest and careful research benefits mankind but premature conclusions (especially in the field of interventional gerontology) harms, not benefits the field (IMO). I am sure the Conboy group would be the first to emphasize that point. Assuming that the cocktail described in this paper is the basis of the excitement, we look forward to controlled evidence-based data that these interventions show safety and efficacy in rigorous trials to benefit those suffering from age-related degenerative disease. @antonioregalado @aubreydegrey aging-us.com/article/206399/…

When Aging is Not Aging There is tremendous confusion out there about age reprogramming. Part of the problem is terminology. So, let’s clarify a few points. When immortal germ line cells branch off from their ceaseless path of producing new individuals and become body (somatic) cells, they are naturally destined to die in a few decades. I call this “somatic restriction.” One of the reasons for somatic restriction is telomerase repression. As a result, they have a finite capacity to replicate (the Hayflick Limit). This is commonly called “cellular aging” or “cell senescence.” A different aspect of somatic restriction is “differentiation.” This refers to the pluripotent cells at the very beginning of life branching out to turn into all the diverse cell type in the body (i.e. neurons, blood, muscle, skin cells and so on). This differentiation process is not usually considered to be “aging.” Instead it is fundamental to the formation of a baby from the pluripotent cells, a process we call “development.” One more critical point. Once the human body is formed (albeit in a miniature version of ourselves), development is said to transition from the embryonic to the fetal stage. I call this the Embryonic-Fetal Transition (EFT). Something profound happens in the EFT. In the embryonic stages, we have the capacity for profound regeneration like the Axolotl salamander. Prior to the EFT severe tissue damage is seamlessly and scarlessly regenerated. After the EFT that amazing capacity is repressed as part of an organism-wide repression similar to that seen with telomerase. This repression of regenerative potential is NOT the same as differentiation. Let’s call it “maturation” instead. So, two pathways play a role in aging due to somatic restriction; namely, the repression of telomerase leading to cellular aging and the loss of regenerative potential (often around the EFT) we are calling maturation. Now, reprogramming factors like OSKM can reverse all of the above taking a skin cell, for example back to pluripotency (induced Pluripotent Stem (iPS) cells). The result can be a true reversal of the primary hallmarks of aging (see our paper pasted below). That is, the telomere clock can be reset by the reactivation of telomerase, differentiation and maturation reversed, and markers of the pre-EFT regenerative state reactivated. But “partial reprogramming” is a goose of a different color. With transient OSKM expression pluripotency is not reached (at least, that’s not the intent). Instead, the “regeneration switches” can reverse maturation, and induce transiently a regenerative state. So, can partial reprogramming reverse aging? Well, as I stated above, in our 2010 paper below we showed that was possible when you take cells all the way to pluripotency. But such complete reprogramming could lead to tumor (teratoma) formation or worse if applied in the same way in patients. So, the evidence suggests that partial reprogramming may re-awaken the regenerative state, but doesn’t reactivate telomerase to reverse cellular aging (at least in human cells). So, I suggest the answer is “no”. Current partial reprogramming protocols likely induce tissue regeneration (iTR), but don’t reverse aging as we defined it above. That explains in part why the clinical trial by David Sinclair’s group is for retinal regeneration, not age reversal. It is also the reason some gerontologists protest the statement it is age reversal. Is it possible to reverse aging using modified versions of these technologies? I suggest the answer in broad strokes is “yes.” Defending that statement would take a monograph. But let me just say, the simple addition of telomerase into the cocktail of genes could reset the telomere clock of cell aging. Even better, some third-generation protocols that combine telomerase with genes directly involved in regeneration could potentially improve the safety and efficacy of such therapies. @KarlPfleger @davidasinclair pubmed.ncbi.nlm.nih.gov/2023…

Reverse Aging by Targeting This or That Gene: AP2A1 as an Example   There are dozens if not hundreds of molecular changes within the cells of our body as we age. Almost all are are downstream effects of the initial causes of aging. When publishing a result on any one such molecular alteration, some scientists find it tempting to tout it as the holy grail or fountain of youth (i.e. an initial cause). It is important for the thoughtful reader therefore to quickly focus one’s attention on the question of whether the data actually supports the conclusion it is cause rather than effect. Let me give an example, @scitechgirl posted an interesting piece about one such paper (pasted below). The group claims that down-regulating AP2A1, a protein associated with cell surface integrins and the cytoskeleton can rescue cells from senescence. Is has been known for decades that the cytoskeleton (stress fibers) are abundant in senescent cells. It may indeed be the case that there is therefore more of the protein visible in old cells since it is part of that abundance of cytoskeleton components. Although the group found the levels of AP2A1 outpacing the stress fibers some ~2.5X.   The significant difference with this paper is that they claim that the knockdown of the gene actually rescues the cells from senescence. For the most part I remain unconvinced. First, they use a knockdown of AP2A1 RNA as a method and don’t show the baseline mRNA levels of AP2A1 in young and old cells. The reason is probably that it is unchanged (at least that is what I see in our and other published data). The protein levels could nevertheless be up-regulated post-transcriptionally of course.   My second concern (and most significant concern) is that they never actually show that the knockdown extends cell lifespan despite hinting at it with p21 expression data. The beta-galactosidase assay they utilized is often used as a marker of senescence but it is by no means specific to it. Why not just show us that cell aging is reversed by actually showing us the replicative lifespan results? I suggest the paper would have been stronger if they had. If it didn’t effect lifespan they could still make the case it was important in intracellular traffic and lysosome function.   Lastly, over- and under-expression of AP2A1 has been studied in transgenic mice and the manipulation of expression results in varied pathologies such as in hematopoiesis, tight junctions in the intestine, etc, but no pathology related to aging.   The paper does have useful observations and speculations regarding the role of stress fibers in autophagy, etc. However, IMO the claim that the protein may provide a target for reversing aging is premature at best, and when exaggerated claims are made in the media, it only adds to the confusion out there, weakening AI that currently assumes all published statements are fact. Having said all that, the paper does, however, provide a useful example of a lack of discrimination between cases and effects in the aging process we all need to keep in mind. @scitechgirl   x.com/scitechgirl/status/209…

Aging, where is your STING? Alex Zhavoronkov recently posted an article on the cGAS-STING pathway interacting with Lamin A. It’s an interesting paper and fits into the assembling puzzle cleanly. As some of you may know, one caveat is that lot of artifacts in cell culture can stimulate the interferon pathway. That aside, since Alex mentioned Lamin A, I would like to point to something relating to the ongoing debate about programmatic aspects of aging vs wear-and-tear models some of which were discovered in a collaboration with him and Insilico Medicine in the early days of AI. If you look at the image I pasted below you can see in A) the expression level of some genes like Lamin A (the gene mutated in progeria) and others during the development of the mouse. POU5F1 is OCT4, (the “O” in the OSKM genes) used to reverse developmental aging to the all-powerful stem cells that can make up the whole body. You can see it is on in the pre-implantation stages. Partial reprogramming transiently expresses genes like OSKM to reverse aging and to induce a regenerative state such as present in early stages of development like days E8-16 in the mouse. The problem, as I pointed out in a previous post, is that OSKM genes take cells to that all-powerful state and could make teratomas (tumors full of hair, teeth, brain and the like) and they appear to push the majority of cells into uncharacterized states with off-target effects. Third generation technologies can use heterochrony genes that do not have these effects. Lastly, in B-E in the figure below, you can see how the trend of expression of a sample of these genes in human cells that change after regeneration is turned off (after day E16 in mouse, 8 weeks in human) continue the post-regenerative trend with developmental time and cellular aging. CDKN1A is an important one and originally named Senescent Derived Inhibitor-1 (SDI-1). This is consistent with the “Hyperfunction programmatic interpretation Pedro de Magalhaes has been discussing. It isn’t inconsistent with error theories of aging, but wouldn’t necessarily be predicted by them. Personally, my hypothesis is that it reflects a repurposing of the regenerative pathways in adults to deal with genotoxic events, not just simply hyperfunction, but more on that later… There are mountains of data out there. I show this sample as part of an introduction to a more comprehensive disclosure in future posts. @biogerontology @jpsenescence @davidasinclair @aubreydegrey